CN1111535C - 4a,5a,8a,8b-tetrahydro-6H-pyrrolo [3',4' : 4,5] furo (3,2-b] pyridine-6,8 [7H]-dione derivatives for use in controlling endoparasites and method - Google Patents

4a,5a,8a,8b-tetrahydro-6H-pyrrolo [3',4' : 4,5] furo (3,2-b] pyridine-6,8 [7H]-dione derivatives for use in controlling endoparasites and method Download PDF

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CN1111535C
CN1111535C CN96199062A CN96199062A CN1111535C CN 1111535 C CN1111535 C CN 1111535C CN 96199062 A CN96199062 A CN 96199062A CN 96199062 A CN96199062 A CN 96199062A CN 1111535 C CN1111535 C CN 1111535C
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furo
pyrrolo
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CN1204335A (en
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P·杰施克
A·哈德
N·门克
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Abstract

The present invention relates to the use of 4a, 5a, 8a, 8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6,8(7H)-dione derivatives of the general formula (I) and salts thereof, in which the radicals R1 to R5 have the meaning given in the description, and to novel 4a, 5a, 8a, 8b-tetrahydro-6H-pyrrolo[3',4':4,5]furo[3,2-b]pyridine-6,8(7H)-dione derivatives and processes for their preparation.

Description

Be used to prevent and treat the Pyrrolidine of endoparasite and furo pyridine-derovatives and its production and use
The present invention relates to 4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] application of pyridine-6,8 (7H)-derovatives aspect the control endoparasite, and relate to new 4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives and their preparation method.
Some 4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives is early known.But their antibody endoparasite purposes be unknown (for example referring to people such as T.Hisano, The chemicals journal(Chem.Pharm.Bull), 35 (3), (1987) p.1049-1057; Heterocycle(Heterocycles) 29 (6), (1989) p.1029-1032; The chemicals journal(Chem.Pharm.Bull), 38 (3), (1990) p.605-611; The chemicals journal(Chem.Pharm.Bull), 39 (1), (1991) p.10-17).
The present invention relates to:
1. general formula (I) 4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives and salt thereof prevents and treats the application of endoparasite in medicine and veterinary drug field:
Wherein
R 1Represent hydrogen, the straight or branched alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, these groups are optionally substituted,
R 2Represent hydrogen, the straight or branched alkyl, cycloalkyl, alkoxy carbonyl, these groups are optionally substituted,
R 1And R 2, together represent 5-or 6-unit ring with the atom that their institute's keys connect, these rings can be randomly by oxygen, sulphur, inferior sulfonyl or alkylsulfonyl are interrupted and are optionally substituted,
R 3Represent hydrogen, the straight or branched alkyl, cycloalkyl, alkoxy carbonyl, these groups are optionally substituted,
R 4Represent hydrogen, the straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, amino, alkylamino, dialkyl amido, cycloalkyl amino, these groups are optionally substituted,
R 5Represent hydrogen, straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, these groups are optional to be replaced, formyl radical, the alkoxyl group dicarbapentaborane, or randomly representative is selected from G 1, G 2, G 3And G 4Group:
Figure C9619906200161
Wherein
R 6Represent hydrogen, the straight or branched alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, these groups are optionally substituted,
R 6And R 7, together represent 5-or 6-unit ring with the atom that their institute's keys connect, these rings can be randomly by oxygen, sulphur, inferior sulfonyl or alkylsulfonyl are interrupted and are optionally substituted,
R 7And R 8Represent hydrogen independently of one another, the straight or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, these groups are optionally substituted,
Or
R 7And R 8The volution that replaces is chosen in representative wantonly together,
Figure C9619906200162
But representation carboxy, thiocarboxyl group ,-C=CH-NO 2,-C=CH-CN ,-C=N-R 9, inferior sulfonyl, alkylsulfonyl ,-P (O)-OR 10Or P (S)-OR 10
R 9Represent hydrogen, hydroxyl, alkoxyl group, alkyl-carbonyl, halogenated alkyl carbonyl, alkyl sulphonyl, nitro or cyano group and
R 10Represent hydrogen or alkyl and
Q represents the straight or branched alkyl, alkenyl, and alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl, these groups are optionally substituted, and perhaps Q randomly represents and is selected from following G 5And G 6Group:
Figure C9619906200171
Wherein: Can represent carboxyl, thiocarboxyl group or alkylsulfonyl,
Y represents oxygen, sulphur or-NR 12,
R 11, when Y represents nitrogen, can represent by nitrogen-atoms key cyclic amino even,
R 11And R 12Represent hydrogen independently of one another, the straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, these groups are optionally substituted, or
R 11And R 12Represent 5-with contiguous N atom, 6-or 7-unit ring system, or represent 7 to 10-bicyclic ring systems of unit, these rings also can be randomly by oxygen, sulphur, inferior sulfonyl, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 14-, or be interrupted by quaternary nitrogen and can be optionally substituted,
R 13Represent hydrogen or alkyl,
R 14Represent hydrogen, the straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxy carbonyl, alkyl-carbonyl, naphthene base carbonyl, cyano group, aryl, aralkyl, heteroaryl, heteroarylalkyl, these groups can be optionally substituted.
Formula (I) compound can how much and/or optically active isomer form or the different isomer mixture form of forming exist, this depends on substituent character.The present invention not only relates to pure isomer, but also relates to isomer mixture.
In the formula (I), dotted line can be represented singly-bound or represent one or two to be positioned to be loaded with substituent R 2Carbon atom and contiguous carbon atom between, and/or be positioned at and be loaded with substituent R separately 1And R 5Carbon atom and the two keys between the contiguous nitrogen-atoms.
When being loaded with substituent R 1Carbon atom with have a substituent R 5Contiguous nitrogen-atoms between when having two key, formula (I) compound exists with its salt form.
The 4a of the preferred general formula (I) that defines below, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives and salt thereof, their optically active isomer and racemic modification optional are used for medicine and the veterinary drug aspect prevents and treats endoparasite:
Wherein:
R 1Represent hydrogen, contain the straight or branched alkyl of as many as 4 carbon atoms, C 3-6-cycloalkyl, aryl-C 1-2Alkyl, aryl, heteroaryl, heteroaryl-C 1-2Alkyl, these groups are optional the replacement,
R 1And R 2Represent optional 5-that replaces or 6-unit ring with the atom that their institute's keys connect,
R 2And R 3Represent hydrogen independently of one another, contain the straight or branched alkyl of as many as 4 carbon atoms, haloalkyl, hydroxyalkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-2The mercapto alkyl, C 1-2Alkylthio alkyl, C 1-2Alkyl thionyl alkyl, C 1-2The alkyl sulfonyl alkyl, aminoalkyl group, C 1-6The alkylamino alkyl, C 1-6-dialkyl aminoalkyl, C 3-6The cycloalkyl amino alkyl, C 3-6Cycloalkyl, C 1-4Alkoxy carbonyl,
R 4Represent hydrogen, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6Alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-4Carbalkoxy-C 1-4Alkyl, amino-C 1-6Alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6Alkyl, C 1-6-trialkyl ammonium-C 1-6Alkyl halide, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-2Alkyl, aryl, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, amino, C 1-4Alkylamino, C 1-4-dialkyl amido, C 3-7Cycloalkyl amino, these groups can be optionally substituted,
R 5Represent hydrogen, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6Alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, amino-C 1-6Alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6Alkyl, C 1-6-trialkyl ammonium-C 1-6Alkyl halide, nitro-C 1-4Alkyl, cyano group-C 1-4Alkyl, C 1-4Alkoxy carbonyl-C 1-4Alkyl, formamyl-C 1-4-alkyl, carboxyl-C 1-4Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-2Alkyl, aryl, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, formyl radical, C 1-4The alkoxyl group dicarbapentaborane, or representative is selected from following G 1, G 2, G 3And G 4Group:
Figure C9619906200191
Wherein
R 6Represent hydrogen, straight or branched C 1-6Alkyl, C 3-6Cycloalkyl, aryl-C 1-2Alkyl, heteroaryl-C 1-2Alkyl, these groups can be optionally substituted,
R 6And R 7Represent 5-or 6-unit ring with the atom of their institute's bondings, they can be randomly by oxygen, sulphur, and inferior sulfonyl or alkylsulfonyl are interrupted and are optionally substituted,
R 7And R 8Represent hydrogen independently of one another, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6Alkyl, C 1-4Alkanoyloxy-C 1-6Alkyl, C 1-2Alkoxy-C 1-6Alkyl, sulfydryl-C 1-6Alkyl, C 1-2Alkylthio-C 1-6Alkyl, C 1-2Alkyl sulfinyl-C 1-6-alkyl, C 1-2Alkyl sulphonyl-C 1-6Alkyl, carboxyl-C 1-6Alkyl, formamyl-C 1-6Alkyl, amino-C 1-6Alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6Alkyl, guanidine radicals-C 1-6-alkyl, this group can be randomly by 1 or 2 carbobenzoxy-(Cbz) replacement or by 1,2,3 or 4 C 1-2Alkyl group replaces, C 1-4Alkoxycarbonyl amino-C 1-6Alkyl, C 2-6Alkenyl, C 3-6Ring-C 1-2-alkyl (C 3-6-cyclo-C 1-2-alkyl), C 3-6-cycloalkyl-C 1-2-alkyl, and the optional aryl that replaces of representative, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, or
R 7And R 8Represent volution together,
Representation carboxy, thiocarboxyl group ,-C=CH-NO 2,-C=CH-CN ,-C=N-R 9, inferior sulfonyl, alkylsulfonyl ,-P (O)-OR 10Or P (S)-OR 10
R 9Represent hydrogen, hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl-carbonyl, halo-C 1-4Alkyl-carbonyl, C 1-4Alkyl sulphonyl, nitro or cyano group and
R 10Represent hydrogen or C 1-4Alkyl and
Q represents straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6Alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, mercapto alkyl, C 1-2Alkylthio alkyl, C 1-2Alkyl sulfinyl alkyl, C 1-2The alkyl sulphonyl alkyl, carboxyalkyl, formamyl alkyl, amino-C 1-6Alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6Alkyl, guanidine radicals-C 1-6-alkyl, this group can be randomly by 1 or 2 carbobenzoxy-(Cbz), and tert-butoxycarbonyl replaces or by 1,2,3 or 4 C 1-2Alkyl group replaces, C 1-4The alkoxycarbonyl amino alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, aryl, aryl-C 1-2-alkyl, heteroaryl or heteroaryl-C 1-2Alkyl, these groups are optionally substituted, or randomly representative is selected from following G 5And G 6Group: R 11-Y-(G 5)
Figure C9619906200202
Wherein
Figure C9619906200203
But representation carboxy, thiocarboxyl group or alkylsulfonyl,
Y represents oxygen, sulphur or-NR 12,
R 11, when Y represents nitrogen, can represent the cyclic amino that connects by the nitrogen-atoms key,
R 11And R 12Represent hydrogen independently of one another, straight or branched C 1-6-alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, C 3-6-cycloalkyl-C 1-2Alkyl, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, they are optional the replacement, perhaps
R 11And R 12Represent 5-with adjacent nitrogen atom, 6-or 7-unit carbocyclic ring ring system, or represent 7 to 10-bicyclic ring systems of unit, these rings also can be randomly by oxygen, sulphur, inferior sulfonyl, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 14-or be interrupted by quaternary nitrogen and be optionally substituted,
R 13Represent hydrogen or C 1-4Alkyl,
R 14Represent hydrogen, straight or branched C 1-6-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-8-cycloalkyl, C 3-8-cycloalkyl-C 1-2-alkyl, C 1-4-alkoxy carbonyl, C 1-4-alkyl-carbonyl, C 3-6-naphthene base carbonyl, cyano group, aryl, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, they can be optionally substituted.
General formula (I) compound is known in some cases, and available similar known method preparation.
In addition, the invention still further relates to:
2. new general formula (Ia) 4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives and salt thereof, and their optically active isomer and racemoid:
Figure C9619906200211
Wherein
R 1Represent hydrogen, have the straight or branched alkyl of 4 carbon atoms of as many as, C 3-6-cycloalkyl, aryl-C 1-2-alkyl, aryl, heteroaryl, heteroaryl-C 1-2-alkyl; They are optionally substituted,
R 2And R 3Represent hydrogen independently of one another, have the straight or branched alkyl of as many as 4 carbon atoms, haloalkyl, hydroxyalkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-2The mercapto alkyl, C 1-2Alkylthio alkyl, C 1-2-alkyl sulfinyl alkyl, C 1-2-alkyl sulphonyl alkyl, aminoalkyl group, C 1-6The alkylamino alkyl, C 1-6Dialkyl aminoalkyl, C 3-6-cycloalkyl amino alkyl, C 3-6Cycloalkyl, C 1-4-alkoxy carbonyl,
R 4Represent hydrogen, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6-alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-4Alkoxy carbonyl-C 1-4-alkyl, amino-C 1-6-alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6-alkyl, C 1-6-trialkyl ammonium-C 1-6-alkyl halide, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6Cycloalkyl, C 3-6-cycloalkyl-C 1-2-alkyl, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, amino, C 1-4-alkylamino, C 1-4-dialkyl amido, C 3-7Cycloalkyl amino, they are optional the replacement,
Its condition is,
R 1Represent hydrogen,
R 2And R 3During represent methylidene,
R 4Represent methylidene not, normal-butyl, phenyl, 2-, 3-or 4-aminomethyl phenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chloro-phenyl-, 3-chloro-4-fluorophenyl, 2-, 3-or 4-nitrophenyl, 4-p-methoxy-phenyl or Alpha-Naphthyl.
3. prepare new general formula (Ia) 4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] method of furo [3,2-b] pyridines-6,8 (7H)-derovatives and salt thereof:
Figure C9619906200221
Wherein
R 1, R 2, R 3And R 4Definition the same 2 described in,
It is characterized by:
If a) suitable in the presence of thinner, make general formula (II) pyridine N-oxides:
Wherein
R 1, R 2And R 3Definition the same 2 described in,
React with general formula (III) maleimide:
Figure C9619906200223
Wherein
R 4Definition the same 2 described in.
In addition, the invention still further relates to:
4. new general formula (Ib) and (Ic) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives and salt thereof, their optically active isomer and racemoid:
Wherein
R 1Represent hydrogen, have the straight or branched alkyl of as many as 4 carbon atoms, C 3-6-cycloalkyl, aryl-C 1-2-alkyl, aryl, heteroaryl, heteroaryl-C 1-2-alkyl, they are optional the replacement,
R 2And R 3Represent hydrogen independently of one another, have the straight or branched alkyl of as many as 4 carbon atoms, haloalkyl, hydroxyalkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-2The mercapto alkyl, C 1-2Alkylthio alkyl, C 1-2-alkyl sulfinyl alkyl, C 1-2-alkyl sulphonyl alkyl, aminoalkyl group, C 1-6The alkylamino alkyl, C 1-6Dialkyl aminoalkyl, C 3-6-cycloalkyl amino alkyl, C 3-6Cycloalkyl, C 1-4-alkoxy carbonyl,
R 4Represent hydrogen, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6-alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-4Alkoxy carbonyl-C 1-4-alkyl, amino-C 1-6-alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6-alkyl, C 1-6-trialkyl ammonium-C 1-6-alkyl halide, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6Cycloalkyl, C 3-6-cycloalkyl-C 1-2-alkyl, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, amino, C 1-4-alkylamino, C 1-4-dialkyl amido, C 3-7Cycloalkyl amino, they are optional the replacement,
R 5Represent hydrogen, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6Alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, amino-C 1-6Alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6Alkyl, C 1-6-trialkyl ammonium-C 1-6Alkyl halide, nitro-C 1-4Alkyl, cyano group-C 1-4Alkyl, C 1-4Alkoxy carbonyl-C 1-4Alkyl, formamyl-C 1-4-alkyl, carboxyl-C 1-4Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-2Alkyl, aryl, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, formyl radical, C 1-4The alkoxyl group dicarbapentaborane, or representative is selected from following G 1, G 2, G 3And G 4Group:
Wherein
R 6Represent hydrogen, straight or branched C 1-6Alkyl, C 3-6Cycloalkyl, aryl-C 1-2Alkyl, heteroaryl-C 1-2Alkyl, these groups can be optionally substituted,
R 6And R 7Represent 5-or 6-unit ring with the atom of their institute's bondings, they can be randomly by oxygen, sulphur, and inferior sulfonyl or alkylsulfonyl are interrupted and are optionally substituted,
R 7Represent hydrogen, straight or branched C 1-6Alkyl, C 2-4-alkenyl, C 3-6-cycloalkyl, C 3-6-cycloalkyl-C 1-2-alkyl, and the optional aryl that replaces of representative, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, or
R 8Represent hydrogen or methyl,
But representation carboxy, thiocarboxyl group ,-C=CH-NO 2,-C=CH-CN ,-C=N-R 9, inferior sulfonyl, alkylsulfonyl ,-P (O)-OR 10Or P (S)-OR 10
R 9Represent hydrogen, hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl-carbonyl, halo-C 1-4Alkyl-carbonyl, C 1-4Alkyl sulphonyl, nitro or cyano group and
R 10Represent hydrogen or C 1-4Alkyl and
Q represents straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6Alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, mercapto alkyl, C 1-2Alkylthio alkyl, C 1-2Alkyl sulfinyl alkyl, C 1-2The alkyl sulphonyl alkyl, carboxyalkyl, formamyl alkyl, amino-C 1-6Alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6-dialkyl amido-C 1-6Alkyl, guanidine radicals-C 1-6-alkyl, this group can be randomly replaced by 1 or 2 carbobenzoxy-(Cbz), tert-butoxycarbonyl or by 1,2,3 or 4 C 1-2Alkyl group replaces, C 1-4The alkoxycarbonyl amino alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, aryl, aryl-C 1-2-alkyl, heteroaryl or heteroaryl-C 1-2Alkyl, these groups are optional the replacement, or randomly representative is selected from following G 5And G 6Group: R 11-Y-(G 5)
Wherein But representation carboxy, thiocarboxyl group or alkylsulfonyl,
Y represents oxygen, sulphur or-NR 12,
R 11, when Y represents nitrogen, can represent the cyclic amino that connects by the nitrogen-atoms key,
R 11And R 12Represent hydrogen independently of one another, straight or branched C 1-6-alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, C 3-6-cycloalkyl-C 1-2Alkyl, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, they are optional the replacement, perhaps
R 11And R 12Represent 5-with adjacent nitrogen atom, 6-or 7-unit carbocyclic ring ring system, or represent 7 to 10-bicyclic ring systems of unit, these rings also can be randomly by oxygen, sulphur, inferior sulfonyl, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 14-or be interrupted by quaternary nitrogen and be optionally substituted,
R 13Represent hydrogen or C 1-4Alkyl,
R 14Represent hydrogen, straight or branched C 1-6-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-8-cycloalkyl, C 3-8-cycloalkyl-C 1-2-alkyl, C 1-4-alkoxy carbonyl, C 1-4-alkyl-carbonyl, C 3-6-naphthene base carbonyl, cyano group, aryl, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, they can be optionally substituted.
5. prepare new general formula (Ib) and (Ic) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives and salt thereof:
Wherein:
R 1, R 2, R 3, R 4And R 5Definition the same 4 described in,
It is characterized by:
In first reactions steps, in the presence of appropriate catalyst, general formula (Ia) 4a that will obtain according to method 3,5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives hydrogenation:
Wherein
R 1, R 2, R 3And R 4Definition the same 2 described in,
Form general formula (Id) and (Ie) shown in 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-n] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives:
Figure C9619906200263
Wherein
R 1, R 2, R 3And R 4Definition the same,
Perhaps
For selectivity prepares new general formula (Ie) derivative and salt thereof, if at first suitable in the presence of thinner with the reaction of the methyl halide of general formula (Ia) derivative and general formula (IV):
Me-Hal (IV)
Wherein Hal represents halogen, fluorine particularly, and chlorine, bromine or iodine,
The formed logical formula V N of hydrogenation in the presence of suitable diluent then 1-methyl ammonium halide:
Figure C9619906200271
Follow general formula (VI) N with gained 1-methyl-derivatives is at N 1Demethylation on the atom:
Figure C9619906200272
Wherein
R 1, R 2, R 3And R 4Definition the same,
Produce (Ie) compound, thereafter,
In second reactions steps, with the general formula (Id) of gained and (Ie) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives:
Figure C9619906200273
Wherein
R 1, R 2, R 3And R 4Definition the same,
If a) suitable in the presence of thinner, and if suitablely in the presence of the alkali reaction auxiliary agent, react with general formula (VII) compound:
R 5-E (VII)
Wherein
R 5Define the same and
E represents the electrophilic leavings group, or
B) with the reaction of general formula (VIII) compound:
Wherein
The acceptor groups (acceptor group) that the A representative is suitable, as nitro, nitrile, ammonia
Base formyl radical or R 13-O-CO-and
R 8And R 13Definition described with top 4,
Or it is characterized in that
C) if suitable in the presence of catalyzer or in the presence of the alkali reaction auxiliary agent, if suitable in the presence of thinner with general formula (IX) epoxide reaction:
Wherein
R 5Definition described with top 4, perhaps
D) if suitable in the presence of catalyzer, if if suitable in the presence of acid binding agent and suitablely in the presence of thinner, react with general formula (X) compound:
Wherein
G, the definition of Q and X is described with top 4, and
The leavings group that the W representative is suitable, as halogen, alkoxyl group, alkylthio or aryloxy,
Perhaps it is characterized in that
For prepare new general formula (Ib) and (Ic) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives and salt thereof
Wherein group pastes Representation carboxy,
E) if suitable in the presence of catalyzer, and if suitablely in the presence of thinner, react with general formula (XI) carboxylic acid anhydride:
(Q-C＝O) 2O (XI)
Wherein
The definition of Q is described with top 4, or
F) if suitable in the presence of catalyzer, if if suitable in the presence of acid binding agent and suitable in the presence of thinner with amino (original text the is amino sows) derivative of general formula (XII) or its activated carboxyl derivatives reaction:
Figure C9619906200292
Wherein
G, Q, X, R 6, R 7And R 8Definition described with top 4, or
G) if suitable in the presence of catalyzer, if if suitable in the presence of acid binding agent and suitable in the presence of thinner with general formula (XIII) or (XIV) compound reaction:
R 11-N＝C＝X(XIII)
Wherein
Radicals R 11, G 1, X, X 1It is described with the definition of Y with top 1,
Perhaps it is characterized in that
For prepare new general formula (Ib) and (Ic) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives and salt thereof
Group wherein Representation carboxy and Y represent oxygen,
H) in the 3rd reactions steps, and the alkaline carbonate of carbonic acid gas and general formula (XV) reaction:
M 2CO 3 (XV)
Wherein
M represents the monovalent base metallic cation, preferred lithium, and sodium, potassium or caesium, particularly potassium or caesium,
Then, in the 4th reactions steps, with the general formula (XVI) of gained and (XVII) an alkali metal salt of compound:
Wherein
Radicals R 1, R 2, R 3And R 4Definition described with top 4,
M represents a metallic cation Equivalent that connects with the salt form key,
If suitable for the alkali reaction auxiliary agent, and if suitable in the presence of thinner with general formula (VIIa) alkylation reactions:
R 11-Hal (VIIa)
Wherein
R 11Definition with top 4 described and
Hal represents halogen, as fluorine, and chlorine, bromine or iodine,
Perhaps it is characterized in that:
I) with general formula (Id) and (Ie) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives:
Wherein
Radicals R 1, R 2, R 3, R 4, G, the definition of W and X is described with top 4,
If suitable in the presence of catalyzer, if suitable in the presence of acid binding agent, and if suitablely in the presence of thinner, react with general formula (XVIII) compound:
R 11-Y-H (XVIII)
Wherein
Radicals R 11Described with the definition of Y with top 4.
General formula (I) provide 4a of the present invention, 5a, and 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-derovatives and salt thereof.
4a of the present invention, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives and acid salt thereof and metal-salt title complex have very good Endoparasiticidal effect (especially anthelmintic action), and are preferred for the veterinary drug field.
Optional substituted alkyl itself in the general formula, or as the group integral part, be meant the straight or branched alkyl that preferably contains 1 to 6 (particularly 1 to 4) carbon atom, the example that can mention has optional methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1-methyl butyl, 2-methyl butyl, the 3-methyl butyl, 1 that replaces, 2-dimethyl propyl, 1, the 1-dimethyl propyl, 2, the 2-dimethyl propyl.1-ethyl propyl, hexyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl propyl and 2-ethyl-butyl.Wherein as preferred, that can mention has methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and a tertiary butyl.
The basic body of optional substituted alkenyl in the general formula, or, be meant the straight or branched alkenyl that preferably contains 1-6 (particularly 1-4) carbon atom as the group integral part.The example that can mention comprises the optional vinyl that replaces, the 2-propenyl, crotyl, the 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-propenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-crotyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl.As preferably, that wherein can mention has optional vinyl, 2-propenyl, crotyl or a 1-methyl-2-propenyl that replaces.
Optional substituted alkynyl itself in the general formula, or, be meant the straight or branched alkynyl that preferably contains 1-6 (particularly 1-4) carbon atom as the group integral part.The example that can mention comprises the optional ethynyl that replaces, 2-propynyl, the 2-butyne base, the 3-butynyl, 1-methyl-2-propynyl, the valerylene base, the valerylene base, the 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butyne base, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1,1-dimethyl-2-butyne base, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl.
As preferably, that can mention comprises optional ethynyl, 2-propynyl or the 2-butyne base that replaces.
Optional substituted cycloalkyl itself in the general formula, or as the group integral part, be meant the monocycle that preferably contains 3-10 (particularly 3,5 or 7) carbon atom-, two rings-and tricyclic naphthenes base.The example that can mention comprises the optional cyclopropyl that replaces, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, two ring [2.2.1] heptyl, two ring [2.2.2] octyl group and adamantyls.
Haloalkyl in the general formula itself, or, contain 1-4 (particularly 1 or 2) carbon atom as the group integral part, and preferably contain 1-9 (particularly 1-5) identical or different halogen atom, preferred fluorine, chlorine and bromine, particularly fluorine and chlorine.The example that this class group can be mentioned comprises trifluoromethyl, trichloromethyl, chlorodifluoramethyl-, dichlorofluoromethyl, chloromethyl, brooethyl, 1-fluoro ethyl, the 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, 2,2,2-three chloroethyls, 2-chloro-2,2-two fluoro ethyls, pentafluoroethyl group and the five fluorine tertiary butyls.
Optional substituted alkoxy itself in the general formula, or, be meant the straight or branched alkoxyl group that preferably contains 1-6 (particularly 1-4) carbon atom as the group integral part.The example that can mention comprises optional methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and the tert.-butoxy that replaces.
The halogenated alkoxy of the optional replacement in the general formula itself, or, be meant the straight or branched halogenated alkoxy that preferably contains 1-6 (particularly 1-4) carbon atom as the group integral part.The example that can mention comprises optional difluoro-methoxy, trifluoromethoxy, trichlorine methoxyl group, chlorine difluoro-methoxy, 1-fluorine oxyethyl group, the 2-fluorine oxyethyl group, 2 that replaces, 2-difluoroethoxy, 1,1,2,2-tetrafluoro oxyethyl group, 2,2,2-trifluoro ethoxy and 2-chloro-1,1, the 2-trifluoro ethoxy.
The basic body of optional substituted alkane sulphur in the general formula, or, be meant the straight or branched alkylthio that preferably contains 1-6 (particularly 1-4) carbon atom as the group integral part.The example that can mention comprises the optional methylthio group that replaces, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio and uncle's butylthio.
The halogenated alkylthio of the optional replacement in the general formula itself, or, be meant the straight or branched halogenated alkylthio that preferably contains 1-6 (particularly 1-4) carbon atom as the group integral part.The example that can mention comprises optional difluoro methylthio group, trifluoromethylthio, trichloro-methylthio, chlorine difluoro methylthio group, 1-fluorine ethylmercapto group, the 2-fluorine ethylmercapto group, 2 that replaces, 2-difluoro ethylmercapto group, 1,1,2,2-tetrafluoro ethylmercapto group, 2,2,2-trifluoro ethylmercapto group and 2-chloro-1,1,2-trifluoro ethylmercapto group.
The alkyl-carbonyl of the optional replacement in the general formula itself, or, be meant the straight or branched alkyl-carbonyl that preferably contains 1-6 (particularly 1-4) carbon atom as the group integral part.The example that can mention comprises optional methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, sec.-propyl carbonyl, normal-butyl carbonyl, isobutyl-carbonyl, sec-butyl carbonyl and the tertiary butyl carbonyl that replaces.
The naphthene base carbonyl of the optional replacement in the general formula itself, or as the group integral part, be meant the monocycle that preferably contains 3-10 (particularly 3,5 or 7) carbon atom-, two rings-and tricyclic naphthenes base carbonyl.The example that can mention comprises the optional cyclopropyl carbonyl that replaces, cyclobutyl carbonyl, cyclopentylcarbonyl, cyclohexyl-carbonyl, suberyl carbonyl, ring octyl group carbonyl, two ring [2.2.1] heptyl carbonyls, two ring [2.2.2] octyl group carbonyl and adamantyl carbonyls.
The alkoxy carbonyl of the optional replacement in the general formula itself, or, be meant the straight or branched alkyl-carbonyl that preferably contains 1-6 (particularly 1-4) carbon atom as the group integral part.The example that can mention comprises optional methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl, n-butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl and the tert-butoxycarbonyl that replaces.
Aryl, for example be meant singly-, two-or the multinuclear aryl, as phenyl, naphthyl, tetralyl, 2,3-indanyl, fluorenyl etc., preferred phenyl or naphthyl.
Optional substituted aryl in the general formula is meant the optional phenyl or naphthyl, particularly phenyl that replaces.
The aralkyl that on behalf of aryl moiety and/or moieties, the optional substituted aralkyl in the general formula preferably be optionally substituted, and its aryl moiety preferably has 6 to 10, particularly 8 carbon atoms (are preferably phenyl or naphthyl, phenyl particularly), and moieties preferably has 1-4 (particularly 1 or 2) carbon atom, and this moieties can be a straight or branched.As preferred examples, benzyl and the styroyl that optional replacement is arranged that can mention.
Optional substituted heteroaryl itself in the general formula, or as the group integral part, be meant and preferably contain the assorted aromatic nucleus of 1-3 (particularly 1 or 2) identical or different heteroatomic 5-to 7-unit.Heteroatoms in the assorted aromatic nucleus is oxygen, sulphur or nitrogen.As preferred examples, the furyl that optional replacement is arranged that can mention, thienyl, pyrazolyl, imidazolyl, 1,2,3-and 1,2,4-triazolyl isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3,4-, 1,2,4-and 1,2,5-oxadiazole base, the azepines base, pyrryl, pyridyl, piperazinyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-, 1,2,4-and 1,2, the 3-triazinyl, 1,2,4-, 1,3,2-, 1,3,6-and 1,2,6-oxazinyl Evil English in heptan base (oxepinyl), thiepin base (thiepinyl) and 1,2,4-two azepines bases (1,2,4-diazepinyl).
That optional substituted radical in the general formula can be loaded with is one or more (preferred 1-3, particularly 1-2) identical or different substituting group.As preferred examples, the substituting group that can mention comprises:
The alkyl that preferably contains 1-4 (particularly 1-2) carbon atom, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the sec-butyl and the tertiary butyl; The alkoxyl group that preferably contains 1-4 (particularly 1-2) carbon atom, as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy; Alkylthio, as methylthio group, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio and uncle's butylthio; Preferably contain the haloalkyl that 1 to 4 (particularly 1-2) carbon atom also preferably contains 1-5 (particularly 1-3) halogen atom, halogen atom wherein can be identical or different halogen atom, preferred fluorine, chlorine or bromine, fluorine or chlorine particularly, this haloalkyl such as difluoromethyl, trifluoromethyl, trichloromethyl; Hydroxyl; Halogen, preferred fluorine, chlorine, bromine or iodine, particularly fluorine and chlorine; Cyano group; Nitro; Amino; Each alkyl preferably has the monoalkyl of 1-4 (particularly 1 or 2) carbon atom-and dialkyl amido, as methylamino-, and first and second amino, dimethylamino, n-propyl amino, sec.-propyl amino, methyl-normal-butyl amino; Alkyl-carbonyl such as methyl carbonyl; The alkoxy carbonyl that preferably has 2-4 (particularly 2-3) carbon atom is as methoxycarbonyl and ethoxycarbonyl; The alkyl sulfinyl that contains 1-4 (particularly 1-2) carbon atom; Halo sulfinyl with 1-4 (particularly 1-2) carbon atom and 1-5 halogen atom is as the trifluoromethyl sulfinyl; Sulfo group (sulfonyl) (SO 2-OH); The alkyl sulphonyl that preferably has 1-4 (particularly 1 or 2) carbon atom is as methylsulfonyl and ethylsulfonyl; Halogenated alkyl sulfonyl with 1-4 (particularly 1-2) carbon atom and 1-5 halogen atom, as trifluoromethyl sulfonyl, perfluor normal-butyl alkylsulfonyl, perfluor isobutyl-alkylsulfonyl; The aryl sulfonyl that preferably has 6-10 aromatic carbon atom is as benzenesulfonyl; Acyl group, aryl, aryloxy, heteroaryl, heteroaryloxy, they itself can be loaded with an above-mentioned substituting group again, and formimino (HC=N-O-alkyl).
Possible suitable cyclic amino is for containing one or more nitrogen-atoms as heteroatomic heteroaromatic or aliphatic ring system, wherein heterocycle can be saturated or undersaturated, and can be a ring system or a plurality of ring system that condenses, and can randomly contain other heteroatoms such as nitrogen, oxygen and sulphur etc.In addition, cyclic amino can also be represented spiro system or bridged ring system.The atomicity that forms cyclic amino is unrestricted under the situation at monocycle, and they comprise 3-8 atom, and under three ring system situations, they then comprise 7 to 11 atoms.
The nitrogen-atoms that contains that can mention has the 1-azetidinyl, pyrrolidino, 2-pyrroline-1-base, 1-pyrryl as the example of heteroatomic saturated and unsaturated monocycle cyclic amino, piperidino-(1-position only), 1,4-dihydropyridine-1-base, 1,2,5,6-tetrahydropyridine-1-base, high-piperidine sub-base; The two or more nitrogen-atoms that contain that can mention have the 1-imidazolidyl, 1-imidazolyl, 1-pyrazolyl as the example of heteroatomic saturated and unsaturated monocycle cyclic amino, the 1-triazolyl, the 1-tetrazyl, 1-piperazinyl, the high piperazinyl of 1-, 1,2 dihydrogen dazins-1-base, 1,2-dihydro pyrimidine-1-base, perhydro-pyrimidine-1-base and 1,4-Diazesuberane-1-base; Contain 1-3 nitrogen-atoms and 1-2 the sulphur atom that can mention have thiazolidine-3-base, isothiazoline-2-base, sulphur (generation) morpholino, sulphur dioxide (generation) morpholino as the example of heteroatomic saturated and unsaturated monocycle cyclic amino; The example of the saturated and unsaturated fused rings cyclic amino that can mention has indoles-1-base, and 1,2-dihydro benzoglyoxaline-1-base, perhydro-pyrrolo-[1,2-a] pyrazine-2-base; The example of the volution cyclic amino that can mention comprises 2-azaspiro [4,5] last of the ten Heavenly stems-2-base; The example of the heterocyclic group of the cyclic amino bridging that can mention has 2-azabicyclic [2.2.1] heptan-7-base.
Preferred compound is following formula (I) compound and salt thereof, and their optically active isomer and racemoid:
Wherein
R 1Represent hydrogen, straight or branched C 1-4Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl), C 3-6-cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aryl, heteroaryl, these groups replace for optional, R 1And R 2Represent optional 5-that replaces or 6-unit ring with the atom that their institute's keys connect,
R 2And R 3Represent hydrogen independently of one another, straight or branched C 1-4Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl), halo-C 1-4Alkyl (particularly chloromethyl, brooethyl, difluoromethyl, trifluoromethyl or trichloromethyl), hydroxyl-C 1-4Alkyl (particularly methylol), C 1-4Alkanoyloxy-C 1-4Alkyl (particularly acetoxy-methyl), C 1-2Alkoxyalkyl (particularly methoxymethyl), C 1-2Alkylthio alkyl (particularly methylthiomethyl), C 1-2Alkyl thionyl-C 1-4Alkyl (particularly first sulfinyl methyl), C 1-2Alkyl sulfonyl-C 1-4-alkyl (particularly methylsulfonyl methyl), amino-C 1-4-alkyl (particularly amino methyl), C 1-6Alkylamino-C 1-4-alkyl (particularly methylamino-methyl), C 1-6-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl), C 3-6Cycloalkyl amino-C 1-2-alkyl (particularly morpholino methyl, thiomorpholine is for methyl), C 3-6Cycloalkyl (particularly cyclopropyl, cyclobutyl), C 1-4Alkoxy carbonyl (particularly methoxycarbonyl, ethoxycarbonyl),
R 4Represent hydrogen, straight or branched C 1-6Alkyl (methyl particularly, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 1,2-dimethyl propyl, 1, the 1-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl-propyl group, hexyl, 1-methyl amyl), halo-C 1-6Alkyl (particularly methyl fluoride, difluoromethyl, difluoro chloromethyl, trifluoromethyl, trichloromethyl, 1-fluoro ethyl, trifluoroethyl, 2-chloro-1,1,2-trifluoroethyl), hydroxyl-C 1-6Alkyl (particularly methylol, hydroxyethyl, 2-hydroxypropyl), C 1-4Alkanoyloxy-C 1-4-alkyl (particularly acetoxy-methyl, acetoxyl group ethyl, 2-acetoxyl group propyl group), C 1-2Alkoxy-C 1-4-alkyl (particularly methoxymethyl, methoxy ethyl, 2-methoxy-propyl), C 1-4Carbalkoxy-C 1-4Alkyl (particularly methoxycarbonyl methyl, ethoxycarbonylmethyl group, tert-butoxycarbonyl methyl, methoxycarbonyl ethyl, ethoxycarbonyl-ethyl), amino-C 1-6Alkyl (particularly amino methyl, amino-ethyl, 2-aminopropyl), C 1-6-alkylamino-C 1-6Alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-6Dialkyl amido-C 1-6Alkyl (particularly dimethylamino methyl, dimethylaminoethyl), C 1-6-trialkyl ammonium-C 1-6Alkyl halide (front three aminomethylene iodine particularly, the amino ethylidene iodine of trimethylammonium), C 3-7-cycloalkyl amino-C 1-4(N-pyrrolidino ethyl particularly, N-morpholino ethyl, N-piperidino-(1-position only)-ethyl, N-thiomorpholine be for ethyl, N for-alkyl 1-(N 4-methylpiperazine subbase)-and ethyl), C 2-6Alkenyl (vinyl particularly, 2-propenyl, crotyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-propenyl, pentenyl, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, the 2-hexenyl, 1,1-dimethyl-crotyl, 1,2-dimethyl-crotyl, 1-ethyl-crotyl), C 2-6Alkynyl (particularly ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl), C 3-6Cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C 3-6Cycloalkyl-C 1-2Alkyl (particularly cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl), aryl (particularly phenyl), aryl-C 1-2Alkyl (particularly phenmethyl, 1-phenylethyl, 2-phenylethyl), heteroaryl (particularly pyridyl or thiazolyl, N-morpholinyl), heteroaryl-C 1-2-alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), C 1-4-haloalkyl (particularly trifluoromethyl, trichloromethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-2-alkylenedioxy group (particularly methylene-dioxy or ethylenedioxy), C 1-4-halogenated alkoxy (particularly trifluoromethoxy, difluoro-methoxy), C 1-4-alkylthio (particularly methylthio group), C 1-4-halogenated alkylthio (particularly trifluoromethylthio), C 1-4-alkyl sulphonyl (particularly methylsulfonyl), C 1-4-alkylamino (particularly methylamino-), two-C 1-4-alkylamino (particularly dimethylamino), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl),
R 5Represent hydrogen, straight or branched C 1-6Alkyl (methyl particularly, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 1,2-dimethyl propyl, 1, the 1-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-methyl amyl), halo-C 1-6Alkyl (particularly methyl fluoride, difluoromethyl, difluoro chloromethyl, trifluoromethyl, trichloromethyl, 1-fluoro ethyl, trifluoroethyl, 2-chloro-1,1,2-trifluoroethyl), hydroxyl-C 1-6Alkyl (particularly methylol, hydroxyethyl, 2-hydroxypropyl), C 1-4Alkanoyloxy-C 1-4-alkyl (particularly acetoxy-methyl, acetoxyl group ethyl, 2-acetoxyl group propyl group), C 1-2Alkoxy-C 1-4-alkyl (particularly methoxymethyl, methoxy ethyl, 2-methoxy-propyl), amino-C 1-6Alkyl (particularly amino methyl, amino-ethyl, 2-aminopropyl), C 1-6-alkylamino-C 1-6Alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-6Dialkyl amido-C 1-6Alkyl (particularly dimethylamino methyl, dimethylaminoethyl), C 1-6-trialkyl ammonium-C 1-6Alkyl halide (particularly trimethylammonium-ammonium methylene radical or trimethyl ammonium ethylidene iodine), C 3-7-cycloalkyl amino-C 1-4(N-pyrrolidino ethyl particularly, N-morpholino ethyl, N-piperidino-(1-position only) ethyl, N-thiomorpholine be for ethyl, N for alkyl 1-(N 4-methyl-Piperazino)-and ethyl), nitro-C 1-4Alkyl (particularly nitro methyl, 2-nitro-ethyl, 2-nitro propyl group), cyano group-C 1-4Alkyl (particularly cyano methyl, 2-cyano ethyl, 2-cyano group propyl group), C 1-4Alkoxy carbonyl-C 1-4Alkyl (particularly methoxycarbonyl methyl, 2-methoxycarbonyl ethyl, 2-ethoxy carbonyl ethyl), formamyl-C 1-4-alkyl (particularly formamyl ethyl), carboxyl-C 1-4Alkyl (particularly 2-carboxy ethyl), C 2-6Alkenyl (vinyl particularly, 2-propenyl, crotyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, pentenyl, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, the 2-hexenyl, 1,1-dimethyl-crotyl, 1,2-dimethyl-crotyl, 1-ethyl-crotyl), C 2-6Alkynyl (particularly ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl), C 3-6Cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C 3-6Cycloalkyl-C 1-2Alkyl (particularly cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl), C 1-4Alkoxyl group dicarbapentaborane (particularly methoxyl group dicarbapentaborane or oxyethyl group dicarbapentaborane), aryl-C 1-2Alkyl (particularly phenmethyl), heteroaryl (particularly pyridyl, pyrimidyl, pyrazinyl or thiazolyl), heteroaryl-C 1-2-alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), C 1-4-haloalkyl (particularly trifluoromethyl, trichloromethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-2-alkylenedioxy group (particularly methylene-dioxy or ethylenedioxy), C 1-4-halogenated alkoxy (particularly trifluoromethoxy, difluoro-methoxy), C 1-4-alkylthio (particularly methylthio group), C 1-4-halogenated alkylthio (particularly trifluoromethylthio), C 1-4-alkyl sulphonyl (particularly methylsulfonyl), C 1-4-alkylamino (particularly methylamino-), two-C 1-4-alkylamino (particularly dimethylamino), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), methoxycarbonyl can be substituted, perhaps R 5Representative is selected from following G 1, G 2, G 3And G 4Group:
Figure C9619906200401
Wherein
R 6Represent hydrogen, straight or branched C 1-6Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1-first butyl, 2-first butyl, 3-first butyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethyl-propyl group, hexyl, 1-first amyl group), C 3-6Cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), aryl-C 1-2-alkyl (particularly phenmethyl), heteroaryl C 1-2-alkyl (particularly picolyl and thiazole methyl), they all can be optionally substituted.
R 6And R 7Represent 5-or 6-unit ring with the atom of their institute's bondings, they can randomly be interrupted by sulphur and be chosen wantonly replacement by hydroxyl,
R 7Represent hydrogen, have the straight or branched alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, sec-butyl, the tertiary butyl) of as many as 6 carbon atoms, hydroxyl-C 1-2Alkyl (particularly methylol, 1-hydroxyethyl), C 1-4Alkanoyloxy-C 1-4Alkyl (particularly acetoxy-methyl, 1-acetoxyl group ethyl), C 1-4Alkoxy-C 1-4Alkyl (particularly methoxymethyl, 1-methoxy ethyl), aryl-C 1-4-alkoxy-C 1-4-alkyl (particularly benzyloxymethyl, 1-benzyloxy ethyl), sulfydryl-C 1-4Alkyl (particularly thiopurine methyltransferase), C 1-4Alkylthio-C 1-4Alkyl (particularly methyl sulfinyl methyl), C 1-4Alkyl sulphonyl-C 1-4Alkyl (particularly methylsulfonyl ethyl), carboxyl-C 1-4Alkyl (particularly carboxyl methyl, carboxy ethyl), C 1-4Alkoxy carbonyl-C 1-4-alkyl (particularly methoxycarbonyl methyl, ethoxy carbonyl methyl), aryl-C 1-4-alkoxy carbonyl-C 1-4-alkyl (particularly carbobenzoxy-(Cbz) methyl), formamyl-C 1-4Alkyl (particularly carbamyl ylmethyl, formamyl ethyl), amino-C 1-4Alkyl (particularly aminopropyl, amino butyl), C 1-4-alkylamino-C 1-4Alkyl (particularly methylamino-propyl group, methylamino-butyl), C 1-4Dialkyl amido-C 1-4Alkyl (particularly dimethylamino-propyl, dimethylamino butyl), guanidine radicals-C 1-4-alkyl (particularly guanidine radicals propyl group), C 1-4Alkoxycarbonyl amino-C 1-4Alkyl (particularly tertiary butyl carbonylamino-propyl group, tertiary butyl carbonylamino butyl) has the alkenyl (particularly vinyl, 2-propenyl, crotyl, 1-methyl-2-propenyl) of 6 carbon atoms of as many as, C 3-6-cycloalkyl-C 1-2-alkyl (particularly cyclopropyl methyl, cyclobutylmethyl, cyclohexyl methyl), heteroaryl-C 1-2-alkyl (benzo [b] thiophene-1-base-methyl particularly, benzo [b] thiene-3-yl-, pyridine-2-ylmethyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, furans-2-base-methyl, furans-3-base-methyl, thiophene-2-base-methyl, thiene-3-yl--methyl, indol-3-yl-methyl, N-methyl-indol-3-yl-methyl, imidazol-4 yl-methyl, N-Methylimidazole-4-base-methyl), aryl-C 1-2-alkyl (particularly benzyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), hydroxyl, C 1-4Alkyl (the particularly methyl or the tertiary butyl), C 1-4-haloalkyl (particularly trifluoromethyl ethyl, difluoromethyl or trichloromethyl), C 1-4-alkoxyl group (particularly methoxyl group, oxyethyl group or tert.-butoxy), C 1-4-halogenated alkoxy (particularly trifluoromethoxy, difluoro-methoxy), C 1-4-alkylthio (particularly methylthio group), C 1-4-halogenated alkylthio (particularly trifluoromethylthio) C 1-2-alkylenedioxy group (particularly methylene-dioxy or ethylenedioxy), nitro, amino, C 1-4-alkylamino (particularly methylamino-), C 1-4-two-alkylamino (particularly dimethylamino), C 3-6-cycloalkyl amino (particularly pyrrolidino, piperidino-(1-position only)), C 3-6-cycloalkyl sulfo-amino (particularly thiomorpholine generation and dioxo thiomorpholine generation), C 3-6-cycloalkyl diamino (particularly N methyl piperazine subbase) and
R 8Represent hydrogen or methyl, Representation carboxy, thiocarboxyl group ,-C=CH-NO 2,-C=CH-CN ,-C=N-R 9, inferior sulfonyl, alkylsulfonyl ,-P (O)-OR 10Or P (S)-OR 10
R 9Represent hydrogen, hydroxyl, C 1-4Alkoxyl group (particularly methoxyl group, oxyethyl group, sec-butoxy), C 1-4Alkyl-carbonyl (particularly methyl carbonyl, ethyl carbonyl), C 1-4-halogenated alkyl carbonyl (particularly trifluoromethyl carbonyl, trichloromethyl carbonyl), C 1-4Alkyl sulphonyl (particularly methylsulfonyl, ethylsulfonyl, third alkylsulfonyl), nitro or cyano group and
R 10Represent hydrogen or C 1-4Alkyl (particularly methyl or ethyl) and
Q represents straight or branched C 1-4Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, sec-butyl, the tertiary butyl), C 1-4-haloalkyl (particularly trifluoromethyl, trichloromethyl, chlorodifluoramethyl-, dichlorofluoromethyl, 1-fluoro ethyl, chloromethyl, brooethyl, 1-fluoro ethyl, 2,2,2-trifluoroethyl, 2,2,2-three chloroethyls), C 2-6Alkenyl (particularly vinyl, 2-propenyl, 1-methyl-2-propenyl and crotyl), C 2-6Halogenated alkenyl (particularly difluoroethylene base, dichloroethylene, 2-chloro-2-propenyl, 2,3,3-three fluoro-2-propenyl, 2,3,3-three chloro-2-propenyl, 4,4-two fluoro-3-butenyls), C 3-6-cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), heteroaryl-C 1-2Alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), hydroxyl, C 1-4Alkyl (the particularly methyl or the tertiary butyl), C 1-4-haloalkyl (particularly trifluoromethyl, difluoromethyl or trichloromethyl), C 1-4-alkoxyl group (particularly methoxyl group), C 1-4-halogenated alkoxy (particularly trifluoromethoxy, difluoro-methoxy), C 1-4-alkylthio (particularly methylthio group), C 1-4-halogenated alkylthio (particularly trifluoromethylthio), nitro, amino, C 1-4-alkylamino (particularly methylamino-), C 1-4-dialkyl amido (particularly dimethylamino)
Or randomly representative is selected from following G 5And G 6Group: R 11-Y-(G 5)
Figure C9619906200421
Wherein
Figure C9619906200422
But representation carboxy, thiocarboxyl group or alkylsulfonyl,
Y represents oxygen, sulphur or-NR 12,
R 11,, can represent the cyclic amino that connects by the nitrogen-atoms key when Y represents nitrogen, 1-azetidinyl particularly, pyrrolidino, 2-pyrroline-1-base, the 1-pyrryl, piperidino-(1-position only), 1,4-dihydro pyridine-1-base, 1-imidazolidyl, 1-imidazolyl, the 1-pyrazolyl, 1-triazolyl, 1-tetrazyl, the 1-piperazinyl, 1-bromine piperazinyl, 1,2-dihydro pyridazine-1-base, 1,2-dihydro pyrimidine-1-base, perhydro-pyrimidine-1-base, 1,4-Diazesuberane-1-base, thiazolidine-3-base, isothiazoline-2-base, morpholino, sulphur (generation) morpholino, sulfurous gas (generation) morpholino, these groups can be selected replace from following group is optional: halogen (fluorine particularly, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), hydroxyl-C 1-4-alkyl (particularly methylol), amino-C 1-4-alkyl (particularly amino methyl, amino-ethyl), C 1-4-alkyl monosubstituted amino-C 1-4-alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl, dimethylaminoethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), or
R 11And R 12Represent hydrogen independently of one another, straight or branched C 1-4-alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, sec-butyl, the tertiary butyl), carboxyl-C 1-4-alkyl (particularly carboxymethyl), C 2-4Alkenyl (particularly vinyl, 2-propenyl, 1-methyl-2-propenyl and crotyl), C 2-4Alkynyl (particularly ethynyl, 2-propynyl and 2-butyne base), C 3-6Cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C 3-6-cycloalkyl-C 1-2Alkyl (particularly cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl), heteroaryl (particularly pyridyl and thiazolyl), heteroaryl-C 1-2-alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), hydroxyl-C 1-4-alkyl (particularly methylol), amino-C 1-4-alkyl (particularly amino methyl, amino-ethyl), C 1-4-alkyl monosubstituted amino-C 1-4-alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl, dimethylaminoethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), perhaps
R 11And R 12Represent 5-with adjacent nitrogen atom, 6-or 7-unit carbocyclic ring ring system, or represent 7 to 10-bicyclic ring systems of unit, these rings also can be randomly by oxygen, sulphur, inferior sulfonyl, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 14-or by the quaternary nitrogen interruption and randomly by C 1-4-alkyl (particularly methyl), hydroxyl-C 1-4-alkyl (particularly methylol), amino-C 1-4-alkyl (particularly amino methyl, amino-ethyl), C 1-4-alkyl monosubstituted amino-C 1-4-alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl, dimethylaminoethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), halogen (particularly fluorine, chlorine, bromine or iodine) replaces,
Or representative is selected from G 7, G 8, G 9, G 10And G 11Group:
Figure C9619906200441
Wherein
N can represent 0,1,2,3 or 4,
R 13Represent hydrogen or C 1-4Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, sec-butyl, the tertiary butyl) and
R 14Represent hydrogen, straight or branched C 1-6-alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, sec-butyl, the tertiary butyl), C 2-6-alkenyl (particularly vinyl, 2-propenyl, 1-methyl-2-propenyl and crotyl), C 2-6-alkynyl (particularly ethynyl, 2-propynyl and 2-butyne base), C 3-6Cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C 3-6-cycloalkyl-C 1-2-alkyl (particularly cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl), C 1-4-alkyl-carbonyl (particularly methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, sec.-propyl carbonyl, normal-butyl carbonyl, isobutyl-carbonyl, sec-butyl carbonyl, tertiary butyl carbonyl), C 3-6-naphthene base carbonyl (particularly cyclopropyl carbonyl, cyclobutyl carbonyl, cyclopentylcarbonyl and cyclohexyl-carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl, n-butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl), hydroxyl-C 1-4Alkyl (particularly methylol, hydroxyethyl) hydroxyethyl alkylsulfonyl ethyl, C 1-4-alkylamino (particularly methylamino-, ethylamino), C 1-4-alkyl monosubstituted amino-C 1-4-alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl, dimethylaminoethyl, dimethylamino-propyl), C 3-7-cycloalkyl amino-C 1-4(N-pyrrolidino ethyl particularly, N-morpholino ethyl, N-piperidino-(1-position only) ethyl, N-thiomorpholine be for ethyl, N for-alkyl 1-(N 4-methylpiperazine subbase)-and ethyl), C 3-6Cycloalkyl amino carbonyl-C 1-2-alkyl (particularly N-morpholino carbonyl methyl), cyano group, aryl (particularly phenyl), aryl-C 1-2Alkyl (particularly phenmethyl), heteroaryl (particularly pyridyl or thiazolyl), heteroaryl-C 1-2-alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), C 1-4-haloalkyl (particularly trifluoromethyl, trichloromethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-2Alkylenedioxy group (particularly methylene-dioxy or ethylenedioxy), C 1-4-halogenated alkoxy (particularly trifluoromethoxy, difluoro-methoxy), C 1-4-alkylthio (particularly methylthio group), C 1-4Halogenated alkylthio (particularly trifluoromethylthio), C 1-4Alkane alkylsulfonyl (particularly methylsulfonyl), C 1-4-alkylamino (particularly methylamino-), two-C 1-4-alkylamino (particularly dimethylamino), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl).
Its condition is, for general formula (Ia) compound,
R 1Represent hydrogen,
R 2And R 3Represent methylidene,
R 4Represent methylidene not, normal-butyl, phenyl, 2-, 3-or 4-aminomethyl phenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-fluorophenyl, 2-chlorine, 4-fluorophenyl, 2-fluorine, 4-chloro-phenyl-, 3-chlorine, 4-fluorophenyl, 2-, 3-or 4-nitrophenyl, 4-p-methoxy-phenyl.
Particularly preferred compound is these formulas (I) compound and salt thereof, and their optically active isomer and racemoid:
Wherein
R 1Represent hydrogen, straight or branched C 1-4Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl), C 3-6-cycloalkyl (particularly cyclopropyl),
R 2Represent hydrogen, straight or branched C 1-4Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl), halo-C 1-4Alkyl (particularly chloromethyl, brooethyl), hydroxyl-C 1-4Alkyl (particularly methylol), C 1-4Alkanoyloxy-C 1-4Alkyl (particularly acetoxy-methyl), C 1-2Alkoxyalkyl (particularly methoxymethyl), C 1-2Alkylthio alkyl (particularly methylthiomethyl), C 1-2Alkyl sulfinyl-C 1-4Alkyl (particularly first sulfinyl methyl), C 1-2Alkyl sulphonyl-C 1-4-alkyl (particularly methylsulfonyl methyl), C 1-6Alkylamino-C 1-4-alkyl (particularly methylamino-methyl), C 1-6-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl), C 3-6Cycloalkyl amino-C 1-2-alkyl (particularly morpholino methyl, thiomorpholine is for methyl), C 1-4Alkoxy carbonyl (particularly methoxycarbonyl, ethoxycarbonyl),
R 3Represent hydrogen, straight or branched C 1-4Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl),
R 4Represent straight or branched C 1-6Alkyl (methyl particularly, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 1,2-dimethyl propyl, 1, the 1-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl-propyl group, hexyl, 1-methyl amyl), halo-C 1-6Alkyl (particularly methyl fluoride, difluoromethyl, fluoro ethyl), C 1-4Carbalkoxy-C 1-4Alkyl (particularly methoxycarbonyl methyl, ethoxycarbonylmethyl group, tert-butoxycarbonyl methyl), C 3-7-cycloalkyl amino-C 1-4-alkyl (N-pyrrolidino ethyl particularly, N-morpholino ethyl, N-piperidino-(1-position only)-ethyl, the N-thiomorpholine is for ethyl), C 2-6Alkenyl (particularly 2-propenyl, crotyl), C 3-6Cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C 3-6Cycloalkyl-C 1-2Alkyl (particularly cyclopropyl methyl, cyclobutylmethyl), aryl-C 1-2Alkyl (particularly phenmethyl, 1-phenylethyl, 2-phenylethyl), heteroaryl (particularly pyridyl or thiazolyl, N-morpholinyl), heteroaryl C 1-2-alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), C 1-4-haloalkyl (particularly trifluoromethyl, trichloromethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-2-alkylenedioxy group (particularly methylene-dioxy or ethylenedioxy), C 1-4-halogenated alkoxy (particularly trifluoromethoxy, difluoro-methoxy), C 1-4-alkylthio (particularly methylthio group), C 1-4-halogenated alkylthio (particularly trifluoromethylthio), C 1-4-alkyl sulphonyl (particularly methylsulfonyl), C 1-4-alkylamino (particularly methylamino-), two-C 1-4-alkylamino (particularly dimethylamino), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl),
R 5Represent hydrogen, straight or branched C 1-6Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl), C 1-4Alkanoyloxy-C 1-4Alkyl (particularly methoxycarbonyl methyl, ethoxycarbonylmethyl group, methoxycarbonyl ethyl, ethoxycarbonyl-ethyl, tert-butoxycarbonyl methyl), amino-C 1-6Alkyl (particularly amino methyl, amino-ethyl), C 1-6-alkylamino-C 1-6Alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-6-dialkyl amido-C 1-6Alkyl (particularly dimethylamino methyl, dimethylaminoethyl), C 1-6-trialkyl ammonium-C 1-6Alkyl halide (particularly trimethylammonium-ammonium methylene radical or trimethyl ammonium ethylidene iodine), C 3-7-cycloalkyl amino-C 1-4(N-pyrrolidino ethyl particularly, N-morpholino ethyl, N-piperidino-(1-position only) ethyl, N-thiomorpholine be for ethyl, N for alkyl 1-(N 4-methyl-Piperazino)-and ethyl), nitro-C 1-4Alkyl, 2-nitro-ethyl, cyano group-C 1-4Alkyl (particularly 2-cyano ethyl), C 1-4Alkoxy carbonyl-C 1-4Alkyl (particularly 2-methoxycarbonyl ethyl), C 2-6Alkenyl (particularly 2-propenyl), C 2-6Alkynyl (particularly 2-propynyl), C 1-4Alkoxyl group dicarbapentaborane (particularly methoxyl group dicarbapentaborane or oxyethyl group dicarbapentaborane), heteroaryl (particularly pyridyl, pyrimidyl, pyrazinyl or thiazolyl), heteroaryl-C 1-2-alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), C 1-4-haloalkyl (particularly trifluoromethyl, trichloromethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-2-alkylenedioxy group (particularly methylene-dioxy or ethylenedioxy), C 1-4-halogenated alkoxy (particularly trifluoromethoxy, difluoro-methoxy), C 1-4-alkylthio (particularly methylthio group), C 1-4-halogenated alkylthio (particularly trifluoromethylthio), C 1-4-alkyl sulphonyl (particularly methylsulfonyl), C 1-4-alkylamino (particularly methylamino-), two-C 1-4-alkylamino (particularly dimethylamino), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), methoxycarbonyl can be substituted,
Perhaps R 5Representative is selected from following G 1, G 2, G 3And G 4Group:
Wherein
R 6Represent hydrogen, straight or branched C 1-6Alkyl (particularly methyl, ethyl), C 3-6Cycloalkyl (particularly cyclopropyl),
R 6And R 7Represent 5-or 6-unit ring with the atom of their institute's bondings, they can randomly be interrupted by sulphur and be chosen wantonly replacement by hydroxyl,
R 7Represent hydrogen, have the straight or branched alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, sec-butyl) of as many as 6 carbon atoms,
R 8Represent hydrogen or methyl, Representation carboxy ,-C=CH-NO 2,-C=CH-CN ,-C=N-R 9, alkylsulfonyl,
R 9Represent C 1-4-halogenated alkyl carbonyl (particularly trifluoromethyl carbonyl, trichloromethyl carbonyl), C 1-4Alkyl sulphonyl (particularly methylsulfonyl, ethylsulfonyl), nitro or cyano group and
The Q representative is selected from following G 2And G 6Group: R 11-Y-(G 5)
Figure C9619906200482
Wherein But representation carboxy or alkylsulfonyl,
Y represent oxygen or-NR 12,
R 11,, can represent the cyclic amino that connects by the nitrogen-atoms key when Y represents nitrogen, pyrrolidino particularly, 2-pyrroline-1-base, 1-pyrryl, piperidino-(1-position only), 1,4-dihydro pyridine-1-base, the 1-piperazinyl, the high piperazinyl of 1-, morpholino, sulphur (generation) morpholino, sulphur dioxide (generation) morpholino, these groups can be randomly selected replace from following group: halogen (fluorine particularly, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), hydroxyl-C 1-4-alkyl (particularly methylol), amino-C 1-4-alkyl (particularly amino methyl, amino-ethyl), C 1-4-alkyl monosubstituted amino-C 1-4-alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl, dimethylaminoethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), or
R 11And R 12Represent hydrogen independently of one another, straight or branched C 1-4-alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, sec-butyl) carboxyl-C 1-4-alkyl (particularly carboxymethyl), C 2-4Alkenyl (particularly vinyl, 2-propenyl, 1-methyl-2-propenyl), C 2-4Alkynyl (particularly ethynyl, 2-propynyl), C 3-6Cycloalkyl (particularly cyclopropyl), heteroaryl-C 1-2-alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), hydroxyl-C 1-4-alkyl (particularly methylol), amino-C 1-4-alkyl (particularly amino methyl, amino-ethyl), C 1-4-alkyl monosubstituted amino-C 1-4-alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl, dimethylaminoethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), perhaps
R 11And R 12Represent 5-with adjacent nitrogen atom, 6-or 7-unit carbocyclic ring ring system, or represent 7 to 10-bicyclic ring systems of unit, these rings also can be randomly by oxygen, sulphur, inferior sulfonyl, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 14-or be interrupted by quaternary nitrogen, and by C 1-4-alkyl (particularly methyl), hydroxyl-C 1-4-alkyl (particularly methylol), amino-C 1-4-alkyl (particularly amino methyl, amino-ethyl), C 1-4-alkyl monosubstituted amino-C 1-4-alkyl (particularly methylamino-methyl, methylamino-ethyl), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl, dimethylaminoethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), halogen (particularly fluorine, chlorine, bromine or iodine) is optional to be replaced,
Or representative is selected from G 7, G 8, G 9, G 10And G 11Group:
Figure C9619906200501
Wherein
N can represent 0,1,2 or 3,
R 13Represent C 1-4Alkyl (particularly methyl or ethyl) and
R 14Represent hydrogen, straight or branched C 1-6-alkyl (particularly methyl, ethyl), C 2-6-alkenyl (particularly vinyl, 2-propenyl), C 2-6-alkynyl (particularly 2-propynyl), C 3-6Cycloalkyl (particularly cyclopropyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl), hydroxyl-C 1-4Alkyl (particularly methylol, hydroxyethyl), hydroxyethyl alkylsulfonyl ethyl, C 1-4-alkylamino (particularly methylamino-, ethylamino), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl, dimethylaminoethyl), C 3-7-cycloalkyl amino-C 1-4(N-pyrrolidino ethyl particularly, N-morpholino ethyl, N-piperidino-(1-position only) ethyl, N-thiomorpholine be for ethyl, N for-alkyl 1-(N 4-methylpiperazine subbase)-and ethyl), C 3-6Cycloalkyl amino carbonyl-C 1-2-alkyl (particularly N-morpholino carbonyl methyl), cyano group, aryl (particularly phenyl), aryl-C 1-2Alkyl (particularly phenmethyl), heteroaryl (particularly pyridyl or thiazolyl), heteroaryl-C 1-2-alkyl (particularly pyridylmethyl and thiazolyl methyl), these groups can be selected replace from following group is optional: halogen (particularly fluorine, chlorine, bromine or iodine), C 1-4Alkyl (particularly methyl), C 1-4-haloalkyl (particularly trifluoromethyl, trichloromethyl), amino, hydroxyl, C 1-4-alkoxyl group (particularly methoxyl group), C 1-2Alkylenedioxy group (particularly methylene-dioxy or ethylenedioxy), C 1-4-halogenated alkoxy (particularly trifluoromethoxy, difluoro-methoxy), C 1-4-alkylthio (particularly methylthio group), C 1-4Halogenated alkylthio (particularly trifluoromethylthio), C 1-4Alkane alkylsulfonyl (particularly methylsulfonyl), C 1-4-alkylamino (particularly methylamino-), two-C 1-4-alkylamino (particularly dimethylamino), C 1-4-alkyl-carbonyl (particularly methyl carbonyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl),
Its condition is, for general formula (Ia) compound,
R 1Represent hydrogen,
R 2And R 3Represent methylidene,
R 4Not represent methylidene or normal-butyl.
Especially preferred compound is these formulas (I) compound and salt thereof, and their optically active isomer and racemoid:
Figure C9619906200511
Wherein
R 1Represent hydrogen,
R 2Represent straight or branched C 1-4Alkyl (particularly methyl, ethyl),
R 3Represent methylidene,
R 4Represent straight or branched C 1-6Alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, isobutyl-, sec-butyl, normal-butyl), C 3-6Cycloalkyl (particularly cyclopropyl, cyclobutyl, cyclopentyl), C 3-6Cycloalkyl-C 1-2Alkyl (particularly cyclopropyl methyl), phenyl-C 1-2Alkyl (particularly phenmethyl, 2-phenylethyl), phenyl, N-morpholinyl, heteroaryl-C 1-2-alkyl (particularly 2-chloro-pyridine-5-ylmethyl, morpholinyl ethyl and diuril azoles-5-ylmethyl), wherein phenyl or heteroaryl can be by halogens, methyl, halogenated methyl, phenyl, phenoxy group, C 1-4-alkyl phenyl, C 1-4The haloalkyl phenoxy group, C 1-4-alkyl phenoxy replaces,
R 5Represent hydrogen, straight or branched C 1-6Alkyl (particularly methyl, ethyl), cyano group-C 1-4-alkyl (particularly 2-cyano ethyl), C 1-4Alkanoyloxy-C 1-4-alkyl (particularly methoxycarbonyl methyl), C 2-6Alkenyl (particularly 2-propenyl), C 2-6Alkynyl (particularly 2-propynyl), C 1-4Alkoxyl group dicarbapentaborane (particularly methoxyl group dicarbapentaborane or oxyethyl group dicarbapentaborane), heteroaryl-C 1-2-alkyl (particularly 5-chloropyridine-2-ylmethyl and chloro-thiazole-5-ylmethyl),
Perhaps representative is selected from following G 1, G 2, G 3And G 4Group:
Wherein
R 6Represent hydrogen or methyl,
R 7Represent hydrogen, have straight or branched alkyl, particularly methyl or the ethyl of as many as 6 carbon atoms,
R 8Represent hydrogen,
Figure C9619906200522
Representation carboxy or alkylsulfonyl,
The Q representative is selected from following G 5And G 6Group:
Figure C9619906200523
Wherein But representation carboxy or alkylsulfonyl,
Y represent oxygen or-NR 12,
R 11, when Y represents nitrogen, can represent the cyclic amino, particularly pyrrolidino that connect by the nitrogen-atoms key, the 1-pyrryl, piperidino-(1-position only), morpholino, sulphur (generation) morpholino, sulphur dioxide (generation) morpholino,
R 11And R 12Represent hydrogen independently of one another, straight or branched C 1-4-alkyl (particularly methyl, ethyl, propyl group, sec.-propyl, sec-butyl), C 2-4Alkenyl (particularly vinyl, 2-propenyl, 1-methyl-2-propenyl), C 2-4Alkynyl (particularly ethynyl, 2-propynyl), C 3-6Cycloalkyl (particularly cyclopropyl), heteroaryl-C 1-2-alkyl (particularly 5-chloropyridine-2-ylmethyl and diuril azoles-5-ylmethyl), perhaps
R 11And R 12Represent 5-with adjacent nitrogen atom, 6-or 7-unit carbocyclic ring ring system, these rings also can be randomly by oxygen, sulphur, alkylsulfonyl, carbonyl ,-N=,-NR 14-or be interrupted by quaternary nitrogen, and by C 1-4-alkyl (particularly methyl, ethyl), hydroxyl-C 1-4-alkyl (particularly methylol), amino-C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylamino methyl), hydroxyl, C 1-4-alkoxy carbonyl (particularly methoxycarbonyl) is optional to be replaced,
Or representative is selected from G 7, G 8, G 9, G 10And G 11Group:
Figure C9619906200531
Wherein
N can represent 0,1, or 2,
R 13Represent C 1-4Alkyl, particularly methyl and
R 14Represent straight or branched C 1-6-alkyl (particularly methyl), C 2-6-alkenyl (particularly vinyl, 2-propenyl), C 2-6-alkynyl (particularly 2-propynyl), C 3-6Cycloalkyl (particularly cyclopropyl), C 1-4-alkoxy carbonyl (particularly methoxycarbonyl), hydroxyl-C 1-4Alkyl, particularly hydroxyethyl, hydroxyethyl alkylsulfonyl ethyl, C 1-4-alkylamino (particularly methylamino-, ethylamino), C 1-4-dialkyl amido-C 1-4-alkyl (particularly dimethylaminoethyl), C 3-7-cycloalkyl amino-C 1-4-alkyl (particularly N-morpholino ethyl, N-piperidino-(1-position only) ethyl), C 3-6Cycloalkyl amino carbonyl-C 1-2-alkyl (particularly N-morpholino carbonyl methyl),
Its condition is, for general formula (Ia) compound,
R 1Represent hydrogen,
R 2And R 3Represent methylidene,
R 4Not represent methylidene or normal-butyl.
Owing to contain one or more chiral centres in general formula of the present invention (I) compound and the salt thereof, therefore they can obtain with pure stereoisomer form or with various enantiomorphs and non-enantiomer mixture form, if necessary, various enantiomorphs can separate with method well known in the art with non-enantiomer mixture.Therefore, the present invention not only relates to pure enantiomorph and the diastereomer especially for control endoparasite in medical science and the veterinary drug field, but also relates to their mixture.
Yet,, preferably use the stereoisomer form of general formula (I) compound and salt thereof according to the present invention.
The suitable salt of the general formula that can mention (I) compound is conventional non-toxic salt, promptly with the salt of various alkali formation and the salt that forms with addition of acid.As preferably, the salt that can mention comprises and mineral alkali forms salt, as an alkali metal salt (for example sodium, potassium or cesium salt), and alkaline earth salt (for example calcium or magnesium salts), ammonium salt, the salt that forms with organic bases (triethyl ammonium salt for example, pyridinium salt, picoline salt.Alcohol salt, tri ethanol ammonium salt, dicyclohexyl ammonium salt or N, N '-dibenzyl ethylenediamine salt), the salt that forms with mineral acid (hydrochloride for example, hydrobromate, vitriol, phosphoric acid salt), the salt that forms with organic carboxyl acid or organic sulfonic acid (formate for example, acetate, trifluoroacetate, maleate, tartrate, mesylate, benzene sulfonate or right-tosylate), with basic aminoacids or the amino acids formed salt of acid type (for example arginic acid salt, aspartate or glutaminate).
The example of new compound of the present invention is listed among the table 1-52. Table 1 Table 1 compound is corresponding to general formula (Ib) compound, wherein R 1=-H, R 2, R 3, R 4=-methyl; R 5Following listed:
Figure C9619906200552
Figure C9619906200561
Table 2
Table 2 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 3
Table 3 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-n-propyl; R 5Has the listed definition of table 1.
Table 4
Table 4 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-sec.-propyl; R 5Has the listed definition of table 1.
Table 5
Table 5 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 6
Table 6 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 7
Table 7 comprises general formula (Ib-1) compound, R1=-H wherein, R 2, R 3=-methyl; R 4=-sec-butyl; R 5Has the listed definition of table 1.
Table 8
Table 8 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-isobutyl-; R 5Has the listed definition of table 1.
Table 9
Table 9 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-cyclobutyl; R 5Has the listed definition of table 1.
Table 10
Table 10 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-cyclopropyl methyl; R 5Has the listed definition of table 1.
Table 11
Table 11 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-cyclopentyl; R 5Has the listed definition of table 1.
Table 12
Table 12 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-2-phenylethyl; R 5Has the listed definition of table 1.
Table 13
Table 13 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=-allyl group; R 5Has the listed definition of table 1.
Table 14
Table 14 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4=
Figure C9619906200601
R 5Has the listed definition of table 1.
Table 15
Table 15 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2, R 3=-methyl; R 4= R 5Has the listed definition of table 1.
Table 16
Table 16 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=-CH 2-Br, R 3, R 4=-methyl; R 5Has the listed definition of table 1.
Table 17
Table 17 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=-CH 2-Br, R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 18
Table 18 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=-CH 2-Br, R 3=-methyl; R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 19
Table 19 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=-CH 2-Br, R 3=-methyl, R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 20
Table 20 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=-CH 2-Br, R 3=-methyl, R 4=-cyclobutyl; R 5Has the listed definition of table 1.
Table 21
Table 21 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2= R 3, R 4=-methyl; R 5Has the listed definition of table 1.
Table 22
Table 22 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=
Figure C9619906200604
R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 23
Table 23 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2= R 3=-methyl, R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 24
Table 24 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=
Figure C9619906200612
R 3=-methyl; R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 25
Table 25 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2= R 3, R 4=-methyl; R 5Has the listed definition of table 1.
Table 26
Table 26 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2= R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 27
Table 27 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2= R 3=-methyl; R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 28
Table 28 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2= R 3=-methyl; R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 29
Table 29 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=
Figure C9619906200617
R 3, R 4=-methyl; R 5Has the listed definition of table 1.
Table 30
Table 30 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2= R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 31
Table 31 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2= R 3=-methyl, R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 32
Table 32 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2= R 3=-methyl; R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 33
Table 33 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=-CO-O-Me, R 3, R 4=-methyl; R 5Has the listed definition of table 1.
Table 34
Table 34 comprises general formula (Ib-1) compound, wherein R 1=-H, R 2=-CO-O-M, R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 35
Table 35 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2=-CO-O-Me, R 3=-methyl; R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 36
Table 36 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2=-CO-O-Me, R 3=-methyl; R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 37
Table 37 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2= R 3, R 4=-methyl; R 5Has the listed definition of table 1.
Table 38
Table 38 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2=
Figure C9619906200622
R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 39
Table 39 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2= R 3=-methyl, R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 40
Table 40 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2= R 3=-methyl; R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 41
Table 41 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2= R 3, R 4=-methyl; R 5Has the listed definition of table 1.
Table 42
Table 42 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2=
Figure C9619906200626
R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 43
Table 43 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2=
Figure C9619906200627
R 3=-methyl, R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 44
Table 44 comprises general formula (Ib-1) compound, wherein R 1=-H; R 2= R 3=-methyl; R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 45
Figure C9619906200632
Table 45 comprises general formula (Ic-1) compound, wherein R 1=-H; R 2, R 3, R 4=-methyl; R 5Has the listed definition of table 1.
Table 46
Table 46 comprises general formula (Ic-1) compound, wherein R 1=-H; R 2, R 3=-methyl; R 4=-ethyl; R 5Has the listed definition of table 1.
Table 47
Table 47 comprises general formula (Ic-1) compound, wherein R 1=-H; R 2, R 3=-methyl; R 4=-n-propyl; R 5Has the listed definition of table 1.
Table 48
Table 48 comprises general formula (Ic-1) compound, wherein R 1=-H; R 2, R 3=-methyl; R 4=-sec.-propyl; R 5Has the listed definition of table 1.
Table 49
Table 49 comprises general formula (Ic-1) compound, wherein R 1=-H; R 2, R 3=-methyl; R 4=-cyclopropyl; R 5Has the listed definition of table 1.
Table 50
Table 50 comprises general formula (Ic-1) compound, wherein R 1=-H; R 2, R 3=-methyl; R 4=-normal-butyl; R 5Has the listed definition of table 1.
Table 51
Table 51 comprises general formula (Ic-1) compound, wherein R 1=-H; R 2, R 3=-methyl; R 4=-cyclopropyl methyl; R 5Has the listed definition of table 1.
Table 52
Table 52 comprises general formula (Ic-1) compound, wherein R 1=-H; R 2, R 3=-methyl; R 4=-2-phenylethyl; R 5Has the listed definition of table 1.
Some formula (Ia) compound is known, and they can a) prepare with top 3 described methods (for example, referring to people such as T.Hisano, The chemicals journal(Chem.Pharm.Bull.), 35 (3), (1987) P1049-1057; Heterocycle(Heterocycles) 29 (6). (1989) P.1029-1032; The chemicals journal(Chem.Pharm.Bull.), 38 (3), (1990) P605-611; The chemicals journal(Chem.Pharm.Bull.), 39 (1), (1991) P10-17).
If 4a in the new general formula (Ia) of preparation, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6, use 3 among the method 3a of 8 (7H)-derovatives, 5-dimethyl-pyridine N-oxides is as general formula (II) compound and use N-benzyl-maleimide as formula (III) compound, and then this method can be represented with following reaction formula:
Formula (II) provides in carrying out the inventive method 3a the General Definition as the required substituted pyridines N-oxide compound of initial substance.In this structural formula, R 1, R 2, R 3Preferred representative those groups that relevant these substituent preferred parts are mentioned already in formula of the present invention (I) compound is described.
As in the substituted pyridines N-oxide compound of initial substance some be known, and wherein some are commercially available obtains or prepare (for example J.M.Essery and K.Schofield by the known method in the document Chemistry can will(J.Chem.Soc.) (1960) P.49539).
Figure C9619906200651
Most of diverse superoxide such as hydrogen peroxide, tert-butyl peroxide, organic or inorganic superoxide or its salt; as 3-chloro-peroxybenzoic acid, peracetic acid, peroxyformic acid; dibenzoyl superoxide etc. all can be used to the pyridine oxide derivative, to produce general formula (II) N-oxide compound.
Superoxide also can be prepared on the spot by another kind of superoxide, for example, prepares peracetic acid on the spot by acetate and hydrogen peroxide.
The consumption of superoxide preferably with initial pyridine equivalent.Also excess peroxide can be used so that reaction is carried out fully.Suitable solvent is any solvent that take place not to disturb side reaction with oxygenant, water for example, alkyl alcohol, carboxylic acid (as acetate or formic acid), or halohydrocarbon (as methylene dichloride particularly).Temperature of reaction is-30 ℃ to+130 ℃, preferred-10 ℃ to+80 ℃.
In addition, formula (III) provides in carrying out the inventive method 3a the General Definition as the required N-substituted maleimide amine of initial substance.In this structural formula, R 4The preferred representative group that relevant this substituent preferred part is mentioned already in formula of the present invention (I) compound is described.
As in the N-substituted maleimide amine of initial substance some be known, and wherein some commercially available obtain or by the known method in the document prepare (for example, referring to EP0608445A1, people such as N.B.Mehta, Organic chemistry(J.Org.Chem.) 25 (1960) P.1012-1015; People such as T.F.Braish, Synthesising communication(Synlett) (1992) p.979-980).
Usually, the inventive method 3a preferably carries out in the presence of thinner.The consumption of thinner should guarantee that preferably reaction mixture keeps good and stirs in entire reaction course.The possible thinner that carries out the inventive method 3a is all inert organic solvents.
The examples of solvents that can mention comprises: halohydrocarbon, particularly hydrochloric ether, and as zellon, tetrachloroethane, propylene dichloride, methylene dichloride, dichlorobutane, chloroform, tetracol phenixin, trichloroethane, trieline, pentaline, two fluorobenzene, 1, the 2-ethylene dichloride, chlorobenzene, bromobenzene, dichlorobenzene, toluene(mono)chloride, trichlorobenzene; Alcohol, as methyl alcohol, ethanol, Virahol, butanols; Ethers, as ethyl propyl ether, methyl tertiary butyl ether, n-butyl ether, phenylmethylether, phenyl ethyl ether, cyclohexyl methyl ether, dme, ether, dipropyl ether, diisopropyl ether, dibutyl ether, diisobutyl ether, isoamyl ether, glycol dimethyl ether, tetrahydrofuran (THF) ， diox, the polyethers of dichloro-diethyl ether and oxyethane and/or propylene oxide; Amine such as trimethylammonium-, triethyl-, tripropyl-, tributylamine, N-methyl-morpholine, pyridine and tetramethylene-diamine; The nitro hydro carbons, as Nitromethane 99Min., nitroethane, nitropropane, oil of mirbane, chloronitrobenzene, o-Methylnitrobenzene; Nitrile, as acetonitrile, propionitrile, butyronitrile, isopropyl cyanide, benzonitrile ,-the benzyl chloride nitrile, and compound such as tetramethylene sulfide dioxide and methyl-sulphoxide, ring fourth sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, two isobutyl sulfoxides, two fourth sulfoxides, diisoamyl sulfoxide; The sulfone class is as diformazan, diethyl, dipropyl, two fourths, hexichol, two oneself, methylethyl, ethyl propyl, ethyl isobutyl-and pentamethylene sulfones; Aliphatic, alicyclic or aromatic hydrocarbons, as pentane, hexane, heptane, octane, nonane and industrial hydro carbons for example contain the so-called petroleum solvent of the component of boiling point in 40-250 ℃ of scope, cymene, the gasoline fraction of boiling spread in 70-190 ℃, hexanaphthene, methylcyclohexane, sherwood oil, V.M.. naphtha, octane, benzene, toluene, chlorobenzene, bromobenzene, oil of mirbane, dimethylbenzene; The ester class is as methyl acetate, ethyl ester, butyl ester, isobutyl ester and methylcarbonate, dibutylester, ethyl; Amides, as the hexa-methylene phosphoryl triamide, methane amide, N-methylformamide, N, dinethylformamide, N, N-diisopropyl formamide, N, the N-dibutyl formamide, N-Methyl pyrrolidone, N-methyl-hexanolactam, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidine, octylpyrrolidone, octyl group hexanolactam, 1,3-dimethyl-2-imidazolinedione, the N-formyl piperidine, N, N '-1,4-diformyl-piperazine; Ketone, as acetone, phenyl methyl ketone; Methylethylketone, methyl butyl ketone.
In the methods of the invention, also can adopt the mixture of above-mentioned solvent and thinner.
Preferable absorbent is halogenated aryl hydrocarbon, particularly chlorobenzene and bromobenzene, and nitro-aromatic is as oil of mirbane, aromatic hydrocarbons, particularly benzene and toluene, ketone is as phenyl methyl ketone, acid amides such as N, dinethylformamide, sulfoxide is as the mixture of ring fourth sulfoxide and/or these thinners and above-mentioned other thinner.
Method 3a is in a kind of above-mentioned thinner, reacts by pyridine N-oxides and general formula (III) the N-substituted maleimide amine that general formula (II) is replaced.
Reaction times is 4 to 72 hours.Be reflected at-10 ℃ to+250 ℃, preferred 0 ℃ to+200 ℃, preferred especially room temperature is carried out to+150 ℃ temperature.Reaction is preferably carried out having in the presence of the pressure, and this pressure can be by being heated to required temperature of reaction generation under reaction conditions.
For carrying out the inventive method 3a, general every mole of general formula (II) compound uses 1.0 to 3.0mol, preferred 1.0 to 2.0mol amount N-substituted maleimide amine.
After reaction is finished, the vacuum concentration reaction soln.Products therefrom can pass through recrystallization in the usual way, vacuum distilling or column chromatography purification (also can referring to preparation embodiment).
Radicals R wherein 1-R 4General formula (Ia) compound with following definition can specifically be introduced.
Figure C9619906200691
Figure C9619906200702
Figure C9619906200711
The invention still further relates to general formula (I) compound of acid salt form.Can be used for salifiable acid and comprise mineral acid, example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, or organic acid such as formic acid, acetate, propionic acid, propanedioic acid, oxalic acid, fumaric acid, hexanodioic acid, stearic acid, tartrate, oleic acid, methylsulfonic acid, Phenylsulfonic acid or toluenesulphonic acids.
The example of the method for preparing the suitable salt of general formula (Ia) compound that can mention has the N of hydrochloride forming method and the corresponding logical formula V of preparation 1-methyl ammonium halide method, 7-ethyl-4a for example, 5a, 8a, 8b-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] N of furo [3,2-b] pyridines-6,8 (7H)-diketone 1-methyl ammonium halide:
Figure C9619906200721
The formation of salt can be carried out as described below: in the presence of the described a kind of thinner of method 3a, general formula (Ia) compound is reacted, perhaps with alkylating agent such as iodomethane reaction in the presence of for example mineral acid (as gaseous hydrogen chloric acid).
Reaction times is 10 minutes to 24 hours.Be reflected at-60 ℃ to+150 ℃, preferred-10 ℃ to+80 ℃, to the temperature of room temperature, carry out particularly preferably in 0 ℃.Be reflected under the normal pressure and carry out.With regard to salify,, generally use excess acid or alkylating agent with respect to every mole of formula (Ia) compound.
After reaction is finished, separate the salt often be settled out, washing and vacuum-drying (also can referring to preparation embodiment).
Surprisingly, new general formula (Ia) 4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives can change into by one or two pair key in the hydrogenated pyridine part general formula (Id) and (Ie) shown in new 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone and 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives, and can be used in the subsequent reactions of method 5.
Usually, follow the program of method 5, promptly in the presence of the catalyzer and in the presence of the thinner, the new 4a shown in the hydrogenation general formula (Ia) at first, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives, form corresponding general formula (Id) and (Ie) shown in new 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives.
Just according to expectation is such, and general formula (Id) compound exists with the isomer mixture form that comprises 3 αYi Goutis and 3 beta isomers.
For example, if use 7-benzyl-4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone are used for hydrogenation as general formula (Ia) compound, then form 7-benzyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone (3 alpha-isomer) and 7-benzyl-1,2,3,4,4a α, 5a α, 8a α, the β of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone (3 β-isomer) isomer mixture.
3 αYi Goutis, 3 beta isomers
For example, if use 7-methyl-4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone are used for hydrogenation as general formula (Ia) compound, then remove to form general formula (Id) 7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone (3 αYi Gouti) and 7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the β of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] outside pyridine-6,8 (7H)-diketone (3 beta isomer) isomer mixture, also obtain general formula (Ie) 7-methyl isophthalic acid, 2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906200741
3 α/3 beta isomer mixtures
The thinner that is used for hydrogenation is the mentioned inert organic solvents of method 3a, as alcohol, and ethanol particularly.
General formula of the present invention (Ie) 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] formation of furo [3,2-b] pyridines-6,8 (7H)-derovatives influences by following hydrogenation conditions.
Be used to carry out the possible suitable catalyst of catalytic hydrogenation and be all conventional hydrogenation catalysts, as platinum catalyst (platinized platinum, platinum sponge, platinum black, colloidal state platinum, platinum oxide, platinum filament etc.), palladium catalyst (palladium sponge for example, palladium black, palladous oxide, palladium/charcoal, pallamine, palladous sulfate barium, carbonate palladium barium, palladium hydroxide etc.), nickel catalyzator (for example reduced nickel, nickel oxide, Ruan Shi nickel etc.), ruthenium catalyst, cobalt catalyst (for example reduce cobalt, Ruan Shi cobalt etc.), iron catalyst (reduced iron for example, Ruan Shi iron etc.), copper catalyst (for example going back native copper, Ruan Shi copper, Ullman copper etc.).But preferably use noble metal catalyst,, if suitable, it is loaded on the suitable carrier, as carbon or silicon-dioxide as platinum and palladium or ruthenium catalyst.
For carrying out hydrogenation, the alcoholic solution of formula (Ia) compound is reacted in the presence of suitable hydrogenation catalyst (for example palladium hydroxide/charcoal).Reaction times is 1 to 20 hour.Hydrogenation is at+10 ℃-+150 ℃, preferred+carry out under 15 ℃-+100 ℃ the temperature.
The isomer mixture that so obtains (3 αYi Goutis and 3 beta isomers) carries out aftertreatment with ordinary method, for example by chromatography purification (equally can referring to preparation embodiment).Yet they also can directly (promptly need not further separation) and be used for the reaction of method 5a-5j.
By using " chiral hydrogenation catalyst ", for example use chirality diphosphine ligand, (2S for example, 3S)-(-)-2, two (the diphenylphosphino)-butane of 3-[(S, S)-chiral phosphorus] (N.K.Roberts, " Catalytic Aspects of Metal Phosphine Complexes " (1982) are ACS Washington p.337) or R (+)-2,2 ' or S (-)-2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene [R (+)-BINAP or S (-)-BINAP] is (referring to people such as A.Miyashita Tetrahedron40 (1984) p.1245), certainly also can significantly increase a kind of isomer (3 αYi Goutis or the 3 beta isomers) content in the isomer mixture, perhaps even might suppress the formation of another kind of isomer (3 αYi Goutis or 3 beta isomers) fully.
Utilize corresponding logical formula V N 1-ammonium methyl halogenide is as N 1-methyl ammonium iodide can optionally make general formula (Ie) 1,2,4a, and 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives, then carry out N 1-demethylation is (referring to people such as B.Fr φ lund Journal of medicinal chemistry(J.Med.Chem.) 38,1995, p.3287).
Formula of the present invention (Ie) 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6, the selection preparation of 8 (7H)-derovatives can be by hydrogenation 7-methyl-4a α, 5a α, 8a α, 8b α-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] N of furo [3,2-b] pyridines-6,8 (7H)-diketone 1-methyl ammonium iodide illustrates:
Figure C9619906200751
Corresponding N 1The hydrogenation of-methyl ammonium iodide can be carried out as described below: in the presence of sodium borohydride, reaction expression (V) compound in any thinner described in the follow-up method 3a is as 7-methyl-4a α, 5a α, 8a α, 8b α-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] N of pyridine-6,8 (7,8)-diketone 1-methyl ammonium iodide.
Inert organic solvents as alcohol (particularly methyl alcohol or ethanol), is preferably used as the thinner of method for hydrogenation.
Reaction times is 10 minutes to 48 hours.Be reflected at-60 ℃ to+100 ℃, preferred-30 ℃ to+80 ℃, more preferably to the temperature of room temperature, carry out at-10 ℃.Reaction is under atmospheric pressure carried out.For this method for hydrogenation, with respect to every mole of formula V N 1-ammonium methyl halogenide, the excessive a little hydrogenant agent of general use.
After reaction was finished, aftertreatment was carried out according to a conventional method, as chromatogram purification (equally referring to preparation embodiment).
Usually, follow-up N 1The mode that-demethylation is described according to people such as R.F.Olofson ( The organic chemistry magazine(J.Org.Chem.), 49,4984, p.2081), by in the presence of suitable chloro-formic ester, at first react 1,2 of new general formula (VI), 4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone carries out, and the result forms corresponding general formula (1g) 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] carbamate of furo [3,2-b] pyridines-6,8 (7H)-diketone (also can referring to method 5i).
1,2 of general formula of the present invention (VI), 4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] N of furo [3,2-b] pyridines-6,8 (7H)-diketone 1-demethylation can be eliminated 7-methyl-4a α by adopting 1-chloroethene oxygen carbonyl chlorine, 5a α, and 8a α, 8b α-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] corresponding N in furo [3,2-b] pyridines-6,8 (7H)-diketone 1-methyl illustrates:
For carrying out N 1-demethylation, with general formula (VI) 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone heats in the presence of excessive 1-chloroethoxy carbonyl chlorine.Reaction times is 1 to 24 hour.N 1-demethylation is at 0 ℃ to+200 ℃, and is preferred+5 ℃ to+150 ℃, more preferably carries out under+50 ℃ to+130 ℃ temperature.
The 1-chloroethene oxygen carbonyl-1,2 that obtains in this way, 4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] aftertreatment of pyridine-6,8 (7H)-diketone carries out in the usual way, for example adopts chromatography purification (equally can referring to preparation embodiment).
1-chloroethene oxygen carbonyl-1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone reacts in any thinner described in the follow-up method 3a.
Preferred inert organic solvents is used as N as alcohol (particularly methyl alcohol or ethanol) 1The thinner of-demethylation.
Reaction times is 10 minutes to 24 hours.Be reflected at 0 ℃ to+100 ℃, carry out under preferred+temperature of 10 ℃ to+80 ℃.Reaction is generally carried out under normal pressure.
After reaction was finished, the gained hydrochloride carried out aftertreatment (equally referring to preparation embodiment) in the usual way.
If at the new general formula (Ib) 1,2,3 of preparation, 4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] among the method 5a of furo [3,2-b] pyridines-6,8 (7H)-derovatives, adopt 7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone is as general formula (Id) compound, and adopt methyl iodide as general formula (VII) compound, then this method can be represented with following reaction formula:
Formula (Id) provide in the inventive method 5a as initial substance required 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-cyclohexadione compounds.In this structural formula, R 1, R 2, R 3And R 4The preferred representative group that relevant these substituent preferred parts are mentioned already in general formula of the present invention (Ib) compound is described.
Formula (Id) 1,2,3,4 as initial substance, 4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-cyclohexadione compounds are new, and can be by above-mentioned method for hydrogenation by 4a, 5a, 8a, 8b-tetrahydrochysene-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives (Ia) makes.
In addition, formula (IV) provides in the inventive method 5a as initial substance required alkylating agent or heteroaryl agent (R 5=heteroaryl) General Definition.
In formula (VII), R 5The description of definition and general formula of the present invention (Ib) compound in relevant these substituent preferred parts mention already identical, and E represents the electrophilic leavings group.
Suitable leavings group comprises for example halogen (as fluorine, chlorine, bromine and iodine), sulphonate (as aryl-and perfluoroalkyl sulfonate ester), mono-substituted diazo and mono-substituted nitroxyl, and J.March, Senior organic chemistry(Advanced Organic Chemistry), the third edition, John Wiley ﹠amp; Sons, New York 1985, p.310-316 in other those listed groups.
Formula (VII) alkylating agent or heteroaryl agent are general known compound in the organic chemistry, perhaps commercially available obtain or by the preparation of known literature method (for example: Houben-Weyl, Methoden der organischen Chemie[organic chemistry method], Vol.V/3, p.830,862; Vol.V/4, p.361,610).
Usually, preferred the inventive method 5a is in the presence of thinner, if suitablely carry out in the presence of the alkali reaction auxiliary agent.
Carrying out the possible thinner that the inventive method 3a uses is all inert organic solvents.
Preferable absorbent comprises ketone, acetone particularly, methylethylketone or methyl iso-butyl ketone (MIBK), acid amides, particularly N, dinethylformamide, N,N-dimethylacetamide or N-methyl-pyrrolidone, the gasoline fraction of boiling spread in 70 ℃ to 190 ℃, benzene particularly, toluene, chlorobenzene, bromobenzene, oil of mirbane or dimethylbenzene, and the mixture of they and above-mentioned thinner.
Certainly, the mixture of described all kinds of SOLVENTS and various thinners also can be used among the inventive method 5a.
Any suitable acid binding agent all can be used as the alkali reaction auxiliary agent that carries out the inventive method 5a, as amine, and particularly tertiary amine, and basic metal and alkaline earth metal compound.
The example of these acid binding agents that can mention comprises lithium, sodium, potassium, the hydride of magnesium, calcium and barium, oxyhydroxide, oxide compound and carbonate, but also comprise other basic cpd, as amidine class alkali or guanidine class alkali, as the 7-methyl isophthalic acid, 5,5-three azabicyclics (4.4.0) last of the ten Heavenly stems-5 alkene (MTBD); Diazabicylo (4.3.0) nonane (DBN), diazabicylo (2.2.2) octane (DABCO), 1,8-diazabicylo (5.4.0) undecylene (DBU), cyclohexyl tetrabutyl guanidine (CyTBG), cyclohexyl tetramethyl guanidine (CyTMG), N, N, N, N-tetramethyl--1,8-naphthylene diamine, pentamethyl-piperidines, tertiary amine, as triethylamine, Trimethylamine 99, tribenzylamine, tri-isopropyl amine, Tributylamine, tribenzylamine, tricyclohexyltin amine, three amylamines, three hexyl amines, N, accelerine, N, N-dimethyl methyl aniline, N, N-dimethyl-right-aminopyridine, N-crassitude, N-methyl piperidine, the N-Methylimidazole, N-methylpyrrole, N-methylmorpholine, N-methyl hexa-methylene amine, pyridine, 4-pyrrolidino pyridine, the 4-Dimethylamino pyridine, quinoline, α-Jia Jibiding, beta-picoline, isoquinoline 99.9, pyrimidine, acridine, N, N.N, N '-tetramethyl-diamines, N, N ', N '-four ethylene diamine, quinoxaline, N-propyl group-diisopropylamine, N-ethyl-Diisopropylamine, N, N '-dimethylcyclohexylamine, 2, the 6-lutidine, 2,4-lutidine or triethylenediamine.
Wherein preferably use tertiary amine, particularly trialkylamine, as triethylamine, N, the N-diisopropylethylamine, N-propyl group-Diisopropylamine, N, N '-dimethylcyclohexylamine or N-methylmorpholine, and alkaline carbonate, particularly sodium bicarbonate, yellow soda ash, salt of wormwood or saleratus.
Method 5a presses described carrying out: in the presence of the alkali reaction auxiliary agent, and reaction expression (Id) compound and general formula (VII) compound in a kind of above-mentioned thinner.
Reaction times is 4 to 72 hours.Be reflected at-10 ℃ to+250 ℃, preferred 0 ℃ to+200 ℃, particularly preferably in carrying out under 0 ℃ to 150 ℃ the temperature.Be reflected under the normal pressure and carry out.For carrying out the inventive method 5a, with respect to every mole of formula (Id) compound, generally use 1.0-6.0mol, preferred 1.0-4.0mol alkali reaction auxiliary agent and 1.0-4.0mol, preferred 1.0-2.0mol alkylating agent (VII).
After reaction was finished, washing reaction solution also separated organic phase, dry and vacuum concentration.Products therefrom passes through recrystallization in a usual manner, vacuum distilling or column chromatography purification (referring to preparation embodiment).
For the inventive method 5a, if suitable, and known aminoalkyl groupization or reductibility aminoalkyl group method in the document (referring to Houben-Weyl, Methoden derOrganischen Chemie[organic chemistry method], Vol.XI/I, p.648; W.S.Emerson, Organic reaction(Org.Reactions) 4, (1948) P.174) also are suitable for preparing general formula (Ib) and (Ic) compound.
If at the new general formula (Ib) 1,2,3 of preparation,, 4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6, among the method 5b of 8 (7H)-derovatives, adopt 7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone are as general formula (Id) compound, and adopt vinyl cyanide as general formula (VII) compound, and then this method can be represented with following reaction formula:
Figure C9619906200801
Formula (Id) provide in the inventive method 5b as initial substance required 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-cyclohexadione compounds.In this structural formula, R 1, R 2, R 3And R 4Those groups that preferred representative is mentioned in the preferred part of relevant these substituting groups in general formula of the present invention (Ib) compound is described already.
General formula (Id) 1,2,3,4 as initial substance, 4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-cyclohexadione compounds are new, and can be by above-mentioned method for hydrogenation by 4a, 5a, 8a, 8b-tetrahydrochysene-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives (Ia) makes.
In addition, formula (VIII) provides in the inventive method 5b the General Definition as the compound of initial substance.
In formula (VIII), R 8The description of definition and general formula of the present invention (Ib) compound in mention already in the preferred part of relevant these substituting groups identical, and the suitable acceptor groups of A representative, nitro for example, nitrile, formamyl, carboxyl or C 1-4Alkoxy carbonyl.
Formula (VIII) compound is a general known compound in the organic chemistry, perhaps commercially available in some cases obtain or (for example: Houben-Weyl by the preparation of known literature method, Methoden der organischen Chemie[organic chemistry method], Vol.VIII, p.265).
Formula (Id) if suitable with the reaction of (VIII) compound be that the employing thinner carries out in the presence of catalyzer.
The thinner that can be used for carrying out the inventive method 5b is an inert solvent mentioned among the method 3a, as alcohol, and particularly methyl alcohol or ethanol.
Method 5b presses described carrying out: if suitable in the presence of suitable catalyzer, reaction expression (Id) compound and general formula (VIII) compound in a kind of above-mentioned thinner.
Reaction times is 4 to 72 hours.Be reflected at-10 ℃ to+200 ℃, preferred-5 ℃ to+150 ℃, particularly preferably in carrying out under 0 ℃ to 100 ℃ the temperature.Under normal pressure, carry out on the reaction principle, but also can under high pressure or low pressure, carry out.Preferred reaction is carried out at normal pressure or under the pressure of height to 15 crust.When temperature of reaction was higher, reaction was preferably under high pressure carried out, if suitable pressure also can be higher than 15 crust.
For carrying out the inventive method 5b, with respect to every mole of formula Id compound, generally use 1.0-3.0mol, preferred 1.0-2.0mol formula (VIII) compound.
After reaction was finished, washing reaction solution was also told organic phase, dry and vacuum concentration.Products therefrom passes through recrystallization in a usual manner, vacuum distilling or column chromatography purification (referring to preparation embodiment).
If at the new general formula (Ib) 1,2,3 of preparation,, 4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6, adopt 7-ethyl-1,2,3 among the method 5c of 8 (7H)-derovatives, 4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone are as general formula (Id) compound, and adopt (±)-2, and 3-epoxypropyl isopropyl ether is as general formula (IX) epoxide, and then this method can be represented with following reaction formula:
Formula (Id) provide in the inventive method 5c as initial substance required 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-cyclohexadione compounds.In this structural formula, R 1, R 2, R 3And R 4Those groups that preferred representative is mentioned in the preferred part of relevant these substituting groups in general formula of the present invention (Ib) compound is described already.
General formula (Id) 1,2,3,4 as initial substance, 4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-cyclohexadione compounds are new, and can be by above-mentioned method for hydrogenation by 4a, 5a, 8a, 8b-tetrahydrochysene-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives (Ia) makes.
In addition, formula (IX) provides in the inventive method 5c the General Definition as the epoxide of initial substance.
In formula (IX), R 5The description of definition and general formula of the present invention (Ib) compound in the preferred part of relevant these substituting groups mention already identical.
Formula (IX) epoxy compounds is generally known compound in the organic chemistry, and they are commercially available or by the preparation of known literature method (for example: Houben-Weyl in some cases, Methoden der organischen Chemie[organic chemistry method], Vol.VI/3, p.371; D.Swern, Organic reaction(Org.Reactions) 7 (1953) p.378).
Formula (Id) is if suitable with the reaction of (IX) compound, and the employing thinner carries out in the presence of catalyzer or in the presence of the alkali reaction auxiliary agent.
The thinner that can be used for carrying out the inventive method 5c is an inertia aprotonic solvent mentioned among the method 3a, as ether, and methyl tertiary butyl ether particularly, tetrahydrofuran (THF) Huo diox, alcohol, particularly methyl alcohol.
If suitable, mentioned all alkali reaction auxiliary agents (particularly alkalimetal hydride) all can be used as and carry out the required reaction promoter of the inventive method 5c among the method 5a.
Method 5c carries out as described below: if suitable, in the presence of reaction promoter, reaction expression (Id) compound and general formula (IX) epoxide in a kind of above-mentioned thinner.
Reaction times is 4 to 72 hours.Be reflected at-10 ℃ to+200 ℃, preferred-5 ℃ to+150 ℃, particularly preferably in carrying out under 0 ℃ to 100 ℃ the temperature.Under normal pressure, carry out on the reaction principle, but also can under high pressure or low pressure, carry out.But reaction is preferably carried out at normal pressure or under the pressure of height to 15 crust.When temperature of reaction was higher, reaction was preferably under high pressure carried out, if suitable pressure also can be higher than 15 crust.
For carrying out the inventive method 5c, with respect to every mole of formula (Id) compound, generally use 0.5-2.0mol, preferred 0.5-1.5mol epoxide.
After reaction was finished, washing reaction solution was also told organic phase, dry and vacuum concentration.Products therefrom passes through recrystallization in a usual manner, vacuum distilling or column chromatography purification (referring to preparation embodiment).
If at the new general formula (Ib) 1,2,3 of preparation, 4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] adopt the 7-methyl isophthalic acid among the method 5d of furo [3,2-b] pyridines-6,8 (7H)-derovatives, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone are as general formula (Id) compound, and adopt allyl chlorocarbonate as general formula (VII) epoxide, and then this method can be represented with following reaction formula:
Figure C9619906200831
Formula (Id) provide in the inventive method 5d as initial substance required 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-cyclohexadione compounds.In this structural formula, R 1, R 2, R 3And R 4Preferred representative those groups that the preferred part of relevant these substituting groups is mentioned already in general formula of the present invention (Ib) compound is described.
General formula (Id) 1,2,3,4 as initial substance, 4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-cyclohexadione compounds are new, and can be by above-mentioned method for hydrogenation by 4a, 5a, 8a, 8b-tetrahydrochysene-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives (Ia) makes.
In addition, formula (X) provides in the inventive method 5d the General Definition as the compound of initial substance.
In formula (VII), G, X, Y, with the preferred part of relevant these substituting groups in the description of the definition of W and general formula of the present invention (Ib) compound mention already identical.
Formula (X) compound is generally known compound in the organic chemistry, and they are commercially available or by the preparation of known literature method (for example: replace allophanyl halogen: DE-A-2 008 116 entirely in some cases; Urea chloride: Liebigs Ann.299, p.85; Carbamate: Houben-Weyl, Methoden der organischen Chemie[organic chemistry method], Vol.E4).
Formula (Id) is that the employing thinner carries out in the presence of the alkali reaction auxiliary agent with (X) reaction of compound.
The thinner that can be used for carrying out the inventive method 5d is an inertia aprotonic solvent mentioned among the method 3a, as, diox, acetonitrile or tetrahydrofuran (THF), but also can be halohydrocarbon, particularly hydrochloric ether, as methylene dichloride.
All acid binding agents described in the method 5a all can be used as and carry out the required alkali reaction auxiliary agent of the inventive method 5d, but preferred tertiary amine, particularly trialkylamine, as triethylamine, N, N-diisopropylethylamine, N-propyl group-Diisopropylamine, N, N '-dimethylcyclohexylamine or N-methylmorpholine.
Method 5d presses described carrying out: in the presence of the alkali reaction auxiliary agent, and reaction expression (Id) compound and general formula (X) compound in a kind of above-mentioned thinner.
Reaction times is 4 to 72 hours.Be reflected at-10 ℃ to+150 ℃, preferred-5 ℃ to+80 ℃, to the temperature of room temperature, carry out particularly preferably in 0 ℃.Be reflected under the normal pressure and carry out.For carrying out the inventive method 5d, with respect to every mole of formula (Id) compound, generally use 1.0-3.0mol, preferred 1.0-1.5mol acylating agent.
After reaction was finished, washing reaction solution was also told organic phase, dry and vacuum concentration.Products therefrom is in a usual manner by recrystallization, vacuum distilling or column chromatography purification (also can referring to preparation embodiment).
In the compound with halo acyl group (G=X represents carbonyl) or halosulfonyl groups (G=X represents alkylsulfonyl) that makes according to method 5d, halogen group can utilize ordinary method by suitable formula (XVIII) (R in subsequent reactions 11-YH) nucleophilic reagent (as amino, hydroxyl or sulfhydryl compound) displacement.
Figure C9619906200841
Here, halogen exchange exists down in the alkali reaction auxiliary agent and to carry out normally under the popular response condition of this type of reaction, and if suitable, can utilize catalyzer to quicken (referring to preparing embodiment).
If 1,2,3,4 at the new general formula (Ib) of preparation and (Ie), 4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines 6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] adopt the 7-methyl isophthalic acid among the method 5e of furo [3,2-b] pyridines-6,8 (7H)-derovatives, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone or 7-methyl isophthalic acid, 2,4a α, 5a α, 8a α, 8b α-(±)-six hydrogen-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone are as general formula (Id) and (Ie) compound, and adopt anhydride diethylene glycol (diglycolic anhydride) as general formula (XI) carboxylic acid anhydride, and then this method can be represented with following reaction formula:
Figure C9619906200851
And/or
Formula (Id) and (Ie) provide in the inventive method 5e as initial substance required 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone and 1,2,4a α, 5a α, 8a α, 8b α-(±)-six hydrogen-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-diketone.In this structural formula, R 1, R 2, R 3And R 4Preferred representative those groups that relevant these substituting groups are preferably partly mentioned already in general formula of the present invention (Ib) and (Ic) compound are described.
As the general formula (Id) of initial substance and (Ie) 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone and 1,2,4a α, 5a α, 8a α, 8b α-(±)-six hydrogen-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-cyclohexadione compounds is new, and can be by above-mentioned method for hydrogenation by 4a, 5a, 8a, 8b-tetrahydrochysene-3,4-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives (Ia) makes.
In addition, formula (XI) provides in the inventive method 5e the General Definition as the carboxylic acid anhydride of initial substance.
In formula (XI), what the preferred part of relevant these substituting groups was mentioned already in the description of the definition of Q and general formula of the present invention (Ib) compound is identical.
Formula (XI) compound is generally known compound in the organic chemistry, and they are commercially available or by the preparation of known literature method (for example: Houben-Weyl in some cases, Methoden der organischen Chemie[organic chemistry method], Vol.VII/4, p.120, Vol.VIII, p.477).
Formula (Id) and/or (Ie) and (XI) reaction of compound is if suitablely carry out in thinner in the presence of the alkali reaction auxiliary agent.
The thinner that can be used for carrying out the inventive method 5e is an inertia aprotonic solvent mentioned among the method 3a, as ether, and methyl tertiary butyl ether particularly, tetrahydrofuran (THF) Huo diox.
If mentioned all acid binding agents suitable all can be used as, carried out the required alkali reaction auxiliary agent of the inventive method 5e among the method 5a, but preferred tertiary amine, trialkylamine particularly, as triethylamine, N, N-diisopropylethylamine, N-propyl group-Diisopropylamine, N, N '-dimethylcyclohexylamine or N-methylmorpholine.
Method 5e presses described carrying out: if suitable in the presence of catalyzer, reaction expression (Id) and/or (Ie) compound and general formula (XI) carboxylic acid anhydride in any above-mentioned thinner.
Possible catalyzer described here not only comprises alkali reaction auxiliary agent mentioned among the method 5a, but also comprises acid catalyst.In fact, all mineral acids or Lewis acid all can be mentioned as this catalyzer.Mineral acid comprises (preferably) haloid acid, as hydrofluoric acid, and Hydrogen bromide or hydroiodic acid HI, and sulfuric acid, phosphoric acid, phosphoric acid (phosphorus acid), nitric acid, and Lewis acid, comprise (preferably) aluminum chloride, boron trifluoride or its etherate, titanium chloride (IV), tin chloride (IV).
Reaction times is 4 to 72 hours.Be reflected at-10 ℃ to+250 ℃, preferred-5 ℃ to+200 ℃, particularly preferably in carrying out under 0 ℃ to 150 ℃ the temperature.Be reflected under the normal pressure and carry out.For carrying out the inventive method 5e,, generally use 1.0-3.0mol, preferred 1.0-1.5mol carboxylic acid anhydride with respect to every mole of formula (Id) and/or (Ie) compound.
On the other hand, method 5e also can only use excessive general formula (XI) carboxylic acid anhydride to carry out in the presence of diluent free, and its condition is to keep reaction mixture well to stir.
After reaction was finished, washing reaction solution was also told organic phase, dry and vacuum concentration.Products therefrom is in a usual manner by recrystallization, vacuum distilling or column chromatography purification (also can referring to preparation embodiment).
If at the new general formula (Ib) 1,2,3 of preparation, 4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] among the method 5f of furo [3,2-b] pyridines-6,8 (7H)-derovatives, adopt the 7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone is as general formula (Id) compound, and adopt the amino acid derivative of N-carbobenzoxy-(Cbz) sarkosine (Z-Sar-OH) as general formula (XII), then this method can be represented with following reaction formula:
Formula (Id) provide in the inventive method 5f as initial substance required 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-cyclohexadione compounds.In this structural formula, R 1, R 2, R 3And R 4Preferred representative those groups that the preferred part of relevant these substituting groups is mentioned already in general formula of the present invention (Ib) compound is described.
General formula (Id) 1,2,3,4 as initial substance, 4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-cyclohexadione compounds are new, and can be by above-mentioned method for hydrogenation by 4a, 5a, 8a, 8b-tetrahydrochysene-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives (Ia) makes.
In addition, formula (XII) provides in the inventive method 5f the General Definition as the amino acid derivative of initial substance.
In formula (XII), G, Q, X, R 6, R 7And R 8Definition and general formula of the present invention (Ib) compound describe in relevant these substituting groups preferably partly mention already identical.
If the naturally occurring or synthetic amino acid as initial substance is chirality, then can (S) or (R) type (or L or D type) existence.
The examples of amino acids that can mention comprises: Aad, Abu, jAbu, ABz, 2ABz, ε Aca, Ach, Acp, Adpd, Ahb, Aib, β Aib, Ala, β Ala, Δ Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) 2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guy, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, HyI, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, β Lys, Δ Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Δ Pro, Pse, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, β Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val
Nal, Tbg, Npg, Chg, Thia (referring to, Houben-Weyl for example, Methodender Organischen Chemie, [organic chemistry method], Vol.XV/1 and 2, Stuttgart, 1974].
Formula (XII) compound is commercially available in some cases, or by known literature method preparation (for example referring to the N-methylamino acid: people such as R.Bowmann, Chemistry can will(J.Chem.Soc) (1950) p.1346; People such as J.R.McDermott Canadianize Association's will(Can.J.Chem.51 (1973) p.1915; People such as H.Wurziger, Kontakte (Merck, Darmstadt) 3 (1987) p.8).
1,2,3 of general formula (Ic), 4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] reaction of pyridine-6,8 (7H)-cyclohexadione compounds and formula (XII) amino acid derivative, preferably utilize thinner to carry out in the presence of coupler He in the presence of the alkali reaction auxiliary agent.
All couplers of carrying out the used coupler of method 5f and be being suitable for making up amido (for example referring to Houben-Weyl, Methoden der organischen Chemie[organic chemistry method], Vol.15/2; People such as Bodanszky, Peptide Synthesis 2nd ed. (Wiley ﹠amp; Sons, New York 1976) or Gross, Meienhofer, The Peptides:Analysis Synthesis, Biology (Academic Press, New York 1979).Preferred use following method: have the pentachloro--(Pcp) and the active ester method of pentafluorophenyl group (Pfp), adopt N-hydroxy-succinamide, N-hydroxyl-5-norbornylene-2,3-diformamide (HONB), 1-hydroxyl-benzotriazole (HOBt) or 3-hydroxyl-4-oxo-3,4-dihydro-1,2, the 3-phentriazine is as alkoxide component, by DCC additive process and carbodiimide (as dicyclohexylcarbodiimide (DCC)) coupling, or n-propane phosphonic acid anhydride (PPA) activatory active ester method, and adopt pivalyl chloride, the mixed anhydride method of Vinyl chloroformate (EEDQ) and isobutyl ester (IIDQ), or with the mixed anhydride method of following reagent coupling: phosphorus reagent, as benzotriazole-1-base oxygen base-three (dimethylamino-phosphorus) hexafluorophosphate (BOP), two (2-oxos-3-oxazolidinyl) Phosphonium acyl chlorides salt (BOP-Cl), or phosphonate reagent, as diethyl phosphorocyanidate (DEPC) and diphenylphosphine acylazide thing (DPPA) or urea reagent, as Tetrafluoroboric acid 2-(1H-benzotriazole-1-yl)-1,1,3, the 3-tetramethyl-urea.
Preferably with phosphorus reagent such as two (2-oxo-3-oxazolidinyl) Phosphonium acyl chlorides salt (BOP-Cl), benzotriazole-1-base oxygen base-three (dimethylamino-phosphorus) hexafluorophosphate (BOP) and phosphonate reagent is as diethyl phosphorocyanidate (DEPC) and diphenylphosphine acylazide thing (DPPA).
All acid binding agents that are suitable for method 5a can be used as the alkali reaction auxiliary agent that carries out the inventive method 5f equally.
Tertiary amine, particularly trialkylamine, as triethylamine, N, the N-diisopropylethylamine, N-propyl group-Diisopropylamine, N, N '-dimethylcyclohexylamine or N-methylmorpholine are only.
The thinner that can be used for carrying out the inventive method 5f is a solvent mentioned among the method 3a, for example halohydrocarbon, particularly hydrochloric ether, and as methylene dichloride or 1,2-ethylene dichloride, and the mixture of these and other described thinner.
Method 5f is generally undertaken by following mode: in the presence of any above-mentioned coupler and in the presence of any above-mentioned alkali reaction auxiliary agent, and in any above-mentioned thinner, reaction expression (Id) compound and general formula (XII) compound.Reaction times is 4 to 72 hours.Be reflected at-10 ℃ to+120 ℃, preferred-5 ℃ to+50 ℃, to the temperature of room temperature, carry out particularly preferably in 0 ℃.Be reflected under the normal pressure and carry out.
For carrying out the inventive method 5f, with respect to every mole of formula (Id) 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone generally use 1.0-3.0mol, preferred 1.0-1.5mol coupler.
After reaction was finished, washing reaction solution was also told organic phase, dry and vacuum concentration.Products therefrom is in a usual manner by recrystallization, vacuum distilling or column chromatography purification (equally can referring to preparation embodiment).
If the new general formula (Ib) of preparation new 1,2,3;, 4,4a; 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 '; 4 ': 4,5] furo [3,2-b] pyridine-6; among the method 5g of 8 (7H)-derovatives, adopt the 7-methyl isophthalic acid, 2; 3,4,4a α; 5a α, 8a α, the α of 8b α-(±)-octahydro-3; 4a-dimethyl-6H-pyrrolo-[3 '; 4 ': 4,5] furo [3,2-b] pyridine-6; 8 (7H)-diketone are as general formula (Id) compound and adopt trichloroacetyl isocyanate as general formula (XIII) compound, and then this method can be represented with following reaction formula:
Figure C9619906200901
Formula (Id) provide in the inventive method 5g as initial substance required 1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-cyclohexadione compounds.In this structural formula, R 1, R 2, R 3And R 4Those groups that preferred representative is mentioned in the preferred part of relevant these substituting groups in general formula of the present invention (Ib) compound is described already.
General formula (Id) 1,2,3,4 as initial substance, 4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-cyclohexadione compounds are new, and can be by above-mentioned method for hydrogenation by 4a, 5a, 8a, 8b-tetrahydrochysene-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives (Ia) makes.
In addition, formula (XIII) and (XIV) provide in the inventive method 5g General Definition as the compound of initial substance.
In formula (XIII) with (XIV), R 11, Y, G 1, X 1With mention already in the preferred part of relevant these substituting groups in the description of the definition of X and general formula of the present invention (Ib) compound identical.
Formula (XIII) and (XIV) compound be generally known compound in the organic chemistry, and they are commercially available or in some cases by known literature method preparation (Houben-Weyl, Methoden der organischen Chemie[organic chemistry method], Vol.E4).
According to the inventive method 5g, the reaction of formula (Id) and (XIII) or (XIV) compound is preferably in the presence of thinner, if suitablely carry out in the presence of the alkali reaction auxiliary agent.
The thinner that can be used for carrying out the inventive method 5g is a solvent mentioned among the method 3a, and nitrile for example is as acetonitrile, propionitrile, butyronitrile, particularly acetonitrile, and ether, as ethyl propyl ether, n-butyl ether, ether, dipropyl ether, Di Iso Propyl Ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, tetrahydrofuran (THF) ， diox, particularly tetrahydrofuran (THF) are with diox.
Method 5g also can carry out in the presence of the alkali reaction auxiliary agent.All mentioned acid binding agents all can be used as and carry out the required this alkali reaction auxiliary agent of the inventive method 5g among the method 5a, but preferred tertiary amine, trialkylamine particularly, as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, and amidine class alkali and guanidine class alkali, as the nonene (DBN) of diazabicylo-(4.3.0), diazabicylo (2.2.2)-octane (DABCO), 1,8-diazabicylo (5.4.0)-undecylene (DBU), particularly 1,8-diazabicylo (5.4.0)-undecylene (DBU).
Method 5g by making general formula (Id) compound and equimolar amount formula (XIII) or (XIV) compound in any above-mentioned thinner, if suitablely in the presence of the alkali reaction auxiliary agent, carry out.Reaction times is 1 to 72 hour.Be reflected at-50 ℃ to+200 ℃, preferred-20 ℃ to+150 ℃, particularly preferably in carrying out under-10 ℃ to+120 ℃ the temperature.
Under normal pressure, carry out on the reaction principle, but also can under high pressure or low pressure, carry out, but preferably carry out at normal pressure or under the pressure of height to 15 crust.When temperature of reaction was higher, reaction was preferably under high pressure carried out, if suitable 15 crust that also can be higher than.
After reaction is finished, adopt general known method aftertreatment reaction mixture (equally can referring to preparation embodiment).
In the presence of basic metal, alkaline-earth metal or ammonium salt, with the amine that can carry out alkali reaction, the method that carbonic acid gas and alkylating agent prepare the organic amino carbamate is known (referring to EP-A511 948, EP-A 628 542 and the document of wherein being quoted).
Have now found that, general formula (Id) and/or (Ie) shown in alkalescence 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives is as secondary amine compound, also can be in the presence of metal carbonate and carbonic acid gas and alkylation reactions, produce general formula (Ib) and (Ic) carbamate.
If at the new general formula (Ib) 1,2,3 of preparation,, 4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6, adopt 7-methyl isophthalic acid, 2,3 among the method 5h of 8 (7H)-derovatives, 4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone are as general formula (Id) compound, and use carbonic acid gas and salt of wormwood, and adopt the propine bromine as general formula (VIIa) compound, then this method can be represented with following reaction formula:
Figure C9619906200921
Preferably in method 5h, use the general formula (Id) 1,2,3,4 that is defined as follows, 4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives, wherein, radicals R 1, R 2, R 3And R 4Has the preferred and particularly preferred definition in the definition of general formula (Ib) compound.
General formula (Id) 1,2,3,4 as initial substance, 4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-cyclohexadione compounds are new, and can be by above-mentioned method for hydrogenation by 4a, 5a, 8a, 8b-tetrahydrochysene-3,4-dialkyl group-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives (Ia) makes.
Common commercialization carbonic acid gas (being also referred to as " dry ice " if appropriate) also can be used as carbonic acid gas in the methods of the invention.
In addition, formula (VIIa) alkylating agent as the initial substance that carries out the inventive method 5h is generally known compound in the organic chemistry.
In formula (VIIa), R 11The description of definition and general formula of the present invention (Ib) compound in mention already in the preferred part of relevant this substituting group identical, and Hal is the electrophilic leavings group.
Suitable leavings group comprises, for example, halogen (as fluorine, chlorine, bromine and iodine), sulphonate (as aryl-and perfluoroalkyl sulfonate ester), mono-substituted diazo and mono-substituted nitroxyl, and J.March is at " senior organic chemistry ", 3rd ed., John wiley ﹠amp; Sons, New York 1985, those leavings groups of listing in addition in p.310-316.
Can produce alkali reaction and can be used for compound of the present invention is the element lithium, sodium, magnesium, potassium, calcium, rubidium, strontium, caesium, barium, and/or one or more basic cpds of ammonium.Possible basic cpd comprises salt, oxide compound, hydride and the oxyhydroxide that for example can produce alkali reaction.The example that can mention comprises: lithium hydride, sodium hydride, potassium hydride KH, hydrolith, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, hydrated barta, Lithium Oxide 98min, sodium peroxide, potassium oxide, Potassium peroxide, calcium oxide, barium oxide, magnesium oxide, strontium oxide, Quilonum Retard, lithium bicarbonate, rubidium carbonate, rubidium bicarbonate, cesium bicarbonate, cesium carbonate, lithium cyanide, sodium cyanide, potassium cyanide, the cyaniding rubidium, bicarbonate of ammonia, cesium carbonate, volatile salt, potassium sulphide, potassium hydrosulfide, sodium sulphite, sodium sulfhydrate and/or their the naturally occurring or synthetic mixture that obtains are as rhombspar or carbonic acid magnesium oxide (magnesium oxide carbonate) and/or contain the compound of sodium or potassium metal in the corresponding carbonate of discrete form.
Yet, the carbonate of preferred as alkali and/or supercarbonate, especially preferred cesium carbonate or salt of wormwood.
The compound that can produce alkali reaction can use with anhydrous form, or when they be during with water of hydration crystalline salt, then use with hydrate forms.But preferably use anhydrous compound.
The thinner that can be used for carrying out the inventive method 5h is a solvent mentioned among the method 3a, and acid amides for example is as the hexa-methylene phosphoryl triamide, N, dinethylformamide, N, N-dipropyl methane amide, N, N-dibutyl formamide, N-methyl-pyrrolidone or N-methyl-hexanolactam, N particularly, the N-dialkylformamide is as N, dinethylformamide, and sulfoxide, as methyl-sulphoxide, ring fourth sulfoxide, the dipropyl sulfoxide, the benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, diisoamyl sulfoxide, particularly methyl-sulphoxide.
On the other hand, method 5h also can carry out (promptly carrying out) in the presence of other alkali in the presence of for example by the alkali reaction auxiliary agent of used alkali less than the amount of 0.5mol.
All mentioned acid binding agents all can be used as and carry out the required this alkali reaction auxiliary agent of the inventive method 5h among the method 5a, but preferred tertiary amine, trialkylamine particularly, as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, and miaow class alkali and guanidine class alkali, as the 7-methyl isophthalic acid, 5,7-three azabicyclics-(4.4.0) last of the ten Heavenly stems-5-alkene (MTBD); The nonene (DBN) of diazabicylo-(4.3.0), diazabicylo (2.2.2)-octane (DABCO), 1,8-diazabicylo (5.4.0) undecylene (DBU), cyclohexyl tetrabutyl guanidine (CyTBG), cyclohexyl tetramethyl guanidine (CyTMG), cyclohexyl tetrabutyl guanidine, N, N, N, N-tetramethyl--1,8 naphthylene diamines use cyclohexyl tetramethyl guanidine (CyTMG) and cyclohexyl tetrabutyl guanidine (CyTBG) especially.
Method 5h presses described carrying out: under the room temperature, at carbonic acid gas, formula (XV) alkaline carbonate that 2-to 3-is doubly excessive and formula (VIIa) alkylating agent exist down, in the above in described any thinner of method 3a, if suitable in the presence of the alkali reaction auxiliary agent, mix general formula (Id) compound.In the second step reactions steps, the formula of Xing Chenging (XVI) and an alkali metal salt (XVII) usefulness formula (VIIa) alkylation is 1 to 72 hour with putting up with, and wherein temperature of reaction is-50 ℃ to+180 ℃, and preferably-30 ℃ to+150 ℃, particularly-10 ℃ extremely+100 ℃.
Under normal pressure, carry out on the reaction principle, but also can under high pressure or low pressure, carry out, but preferably carry out at normal pressure or under the pressure of paramount 15 crust.When temperature of reaction was higher, reaction was preferably under high pressure carried out, if suitable 15 crust that also can be higher than.
Reaction product adopts general known method to carry out aftertreatment and separate (equally can referring to preparation embodiment).
If at the new general formula (Ib) 1,2,3 of preparation, 4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] adopt 1-(4-nitrophenoxy carbonyl)-7-methyl isophthalic acid among the method 5i of furo [3,2-b] pyridines-6,8 (7H)-derovatives, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone are as general formula (If) compound, and adopt the nucleophilic reagent of morpholine as general formula (XVIII), and then this method can be represented with following reaction formula:
Formula (If) provide in the inventive method 5i as initial substance required 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] General Definition of furo [3,2-b] pyridines-6,8 (7H)-derovatives.In this structural formula, R 1, R 2, R 3, R 4, R 5, G, W preferably represents those groups that the preferred part of relevant these substituting groups is mentioned already in general formula of the present invention (If) compound is described with X.
As the general formula (If) 1,2,3,4 of initial substance, 4a, 5a, 8a, 8b-octahydro-6H pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives can be according to top the inventive method 5d preparation of describing already.
In addition, be generally known compound in the organic chemistry, and in them some are commercially available as carrying out required initial substance formula (XVIII) nucleophilic reagent of the inventive method 5i.In formula (XVIII), R 11With the definition of Y and the preferred part during general formula of the present invention (Ib) compound is described mention already identical.
Method 5i is by in any above-mentioned thinner, and in the presence of formula (XVIII) nucleophilic reagent, reaction expression (If) compound carries out.Reaction times is 4 to 72 hours.Be reflected at+10 ℃ to+200 ℃, preferred+20 ℃ to+150 ℃, particularly preferably in carrying out under the boiling temperature of thinner.
Under normal pressure, carry out on the reaction principle, but also can under high pressure or low pressure, carry out, but preferably carry out at normal pressure or under the pressure of paramount 15 crust.When temperature of reaction was higher, reaction was preferably under high pressure carried out, if suitable pressure also can be higher than 15 crust.
After reaction was finished, washing reaction solution was also told organic phase, dry and vacuum concentration.Products therefrom is in a usual manner by recrystallization, vacuum distilling or column chromatography purification (equally can referring to preparation embodiment).
Adopt the inventive method 5a to 5i, by have (S) and (R) The compounds of this invention that obtains of each unit of configuration (or L and D configuration) still keep the original configuration of initial substance.
" inert solvent " described in the above-mentioned different methods 5a to 5i is inertia all being meant under special reaction condition under each situation, but is not the inert solvent under any required reaction conditions.
These active compounds have hypotoxicity to warm-blooded animal, be suitable for control and be present in human body and the intravital pathogenicity bo endoparasite of animal, described animal comprises the farming animals of livestock industry and cattle breeding, the breeding animal, zoo animal, laboratory animal and experimental animal and pet.In these areas, they are to all or the indivedual etap of insect, and all have activity to what have a resistance with normal responsive kind.By preventing and treating the pathogenicity bo endoparasite, can reduce disease, dead and avoid throughput (for example at meat, milk, wool, leather, eggs are in the production of honey etc.) reduce, like this by using these active compounds to develop animal husbandry more economical and easily.The pathogenicity bo endoparasite comprises washs worm, fluke, and nematode, acanthocephala, particularly:
Pseudophyllidea, for example: Diphyllobothrium, repeatedly Eimeria is washed in the palace, splits head and washs Eimeria, and tongue belongs to, and Eimeria (Bothridium spp.), Diphlogonoporus spp. are washed in phyllidium
Cyclophyllidea, for example: in grow the hole and wash Eimeria, naked head is washed Eimeria, Paranoplocephalaspp., cover the Buddhist nun and wash Eimeria, the tunnel body is washed Eimeria, the tunnel body belongs to, Avitellina spp., Stilesiaspp., Eimeria is washed in ring, Andyra spp., and Bert is washed Eimeria, band is washed Eimeria, the sour jujube ball is washed Eimeria, and the bubble tail is washed Eimeria, and the axe hook is washed Eimeria, the auspicious upright Eimeria of washing, putamina is washed Eimeria, and Echinolepisspp., sour jujube squama wash Eimeria (Echinocotyle spp.), two testis are washed Eimeria, Eimeria is washed in multiple hole, Joyeuxiella spp., and diplopore is washed Eimeria.
Helerocolylea, for example, Gyrodactylus, Dactylogyrus, polydisc is inhaled subordinate.
Digenea, for example, composite aperture fasciola belongs to, Posthodiplostomum spp., Schistosoma, hair testis fluke belongs to Ornithobilharzia, Australia's Schistosoma, huge fluke genus, Leucochloridium, Brachylaimus, the Echinostoma of splitting, Echinoparyphium, Echinochasmus, Hypoderaerum, the sheet fluke belongs to, Fascioloides, Fasciolopsis, intestinal fluke belongs to ring, Typhlocoelum is with a mouthful genus, Calicophoron, Cotylophoron, Gigantocotyle spp., luxuriant and rich with fragrance fluke belongs to, Gastrothylacus spp., Notocotylus, Catatropis spp., Plagiorchis, Dicrocoelium, wealthy mouthful of fluke belongs to, Troglotrema, Paragonimus, the cake fluke belongs to, Nanophyetus salmincola belongs to, Opisthorchis, Clon, Meotrchis, Heterophyes(Heterophyes), Metagonimus.
Mouth time order, for example: Trichocephalus, the capillary fluke belongs to, Trichomonas, Trichinella.
Rhabditida, for example; Micronema spp., Strongyloides.
The strongylid order, for example: Strongylus, Ternidens, knot tooth trace Eimeria, Trichonema, Gyalocephalus, tube pharynx Turbatrix, Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., oesophagostomum, Chabertia, the kidney Turbatrix, Ancylostoma, Ancylostoma, Bunostomum, Globocephalus, Syngamus, Poteriostomum, Metastrongylus, Dictyocaulus, the Miller Turbatrix, former round lung Eimeria, Neostrongylus, the suspensor Turbatrix, Pneumostrongylus, needle handle Turbatrix, Elaphostrongylus spp., Parelaphostrongylus spp., spheroid Turbatrix, near-ring body Turbatrix, Angiostrongylus, Aelurostrongylus, the silk thread Eimeria is intended the silk thread Eimeria, trichostrongylus, Haemonchus, this off-line Eimeria difficult to understand, Marshallagla, Cooperia, Nematodirus, following Strongylus, the sharp Turbatrix in side, breach nematode institute, Ollulanus spp..
The fine stern order, for example: Oxyuris, Enterobius, Passalurus, pipeline Eimeria, Aspiculuris spp., Heterakis.
Ascaridina, for example: Toxascaris, Belascaris, parascris does not have the decorations Ascaris, Ascaridia.
Spirurata, for example: the jaw mouth nematode belongs to, and the bubble wing belongs to Thelazia, Gongylonema, Habronema, secondary Habronema, Drascheia, Dracunculus.
Filarioidea, for example: Stephanofilaria, Parafilaria, abdominal cavity Turbatrix, African Filaria, Dirofilaria, Litomosoides, cloth Shandong Turbatrix, Wuchereria, Onchocerca.
Megacanthopore kiss order, for example; Silk sour jujube Eimeria, chain pearl sour jujube Eimeria, Macracanthorhynchus, preceding cryptorchidism sour jujube worm.
The raise livestock animal comprises Mammals, ox for example, horse, sheep, pig, goat, camel, buffalo, donkey, rabbit, Huang Lu, reinder; The hairiness animal, as mink, squirrel, racoon; Bird such as chicken, goose, turkey, duck; Fresh water and sea water fish such as trout, carp, eel; Reptilia, insect such as honeybee and filaria.
Laboratory and test animal comprise mouse, rat, cavy, golden hamster, dog and cat.
Pet comprises dog and cat.
The compounds of this invention not only preventability uses, but also can therapeutic use.
Active compound of the present invention can be directly or with suitable dosage form through enteron aisle, parenteral is through skin, nasal administration, use by processing environment, or use, as bar by means of the moulded product that contains active compound, plate, band, neck ring, ear pendant thing, astragal (limb tapes), marker (marking devices).
Active compound of the present invention can be in following formulation mode through enteron aisle (for example oral) administration: pulvis, tablet, capsule, paste, potus, granule, solution for oral use, suspension, and emulsion, medicine group (boli), the feed of dosing or tap water.Applied dermally carries out with following form: drops for example, sprays or water spill and point is executed preparation.Parenteral is used with for example injection system (intramuscular, subcutaneous, intravenously, peritoneal injection) or by transplanting mode and is carried out.
Suitable preparation comprises:
Solution, as injection liquid, oral liquid, the enriched material that the dilution back is oral is used as on the skin and endoceliac solution, waters and spills preparation, gel;
Emulsion and suspension for oral or applied dermally and injection; Semi-solid preparation;
Active compound is mixed the preparation in white cream base material or oil-in-water or water-in-oil emulsion matrix;
Solid preparation, as pulvis, pre-composition or enriched material, granule, pill, tablet, medicine group, capsule; Aerosol and inhalation contain the mouldings of active compound.
Injection liquid is by intravenously, and intramuscular and subcutaneous route are used.
Injection liquid is pressed described preparation: active compound is dissolved in the appropriate solvent, if necessary, adds additive, and as solubilizing agent, acid, alkali, buffering salt, oxidation inhibitor, sanitas.Solution is carried out sterile filtration and be circulated in the bottle.
The solvent that can mention comprises: the solvent that tolerates on the physiology, and as water, alcohol (as ethanol, butanols, benzylalcohol, glycerine, propylene glycol, polyoxyethylene glycol), N-Methyl pyrrolidone, and their mixture.
If suitable, also active compound can be dissolved on the physiology in that can tolerate and plant that be suitable for injection or the synthetic oil.
The solubilizing agent that can mention comprises: the enhanced activity compound is the dissolved solvent in primary solvent, or prevents the sedimentary solvent of active compound.Its example has polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxy ethylization sorbitan ester.
Sanitas comprises: benzylalcohol, and Trichloroisobutyl Alcohol, right-hydroxybenzoate, propyl carbinol.
Oral liquid is directly taken.Be diluted to behind the application concentration enriched material Orally administered in advance.Oral liquid and enriched material be as method preparation as described in the top injection liquid part, but can omit the aseptically process step.
The solution that skin uses by drip, brush, massage, spray quinoline or spray on skin, the preparation of these solution is identical with above-mentioned injection solution preparation method.
Adding thickening material in preparation process may be more favourable.Thickening material comprises inorganic thickening agent, as wilkinite, and colloid silicic acid, aluminum monostearate; Organic thickening agent, as derivatived cellulose, polyvinyl alcohol and multipolymer thereof, acrylate and methacrylic ester.
Gel applies or spreads upon on the skin or imports in the body cavity.Gel prepares by the thickening material that adds the amount of the transparent composition that can form white cream sample denseness in according to the solution of the preparation of the method described in the injection liquid solution.The thickening material that is adopted is above-mentioned thickening material.
Water and spill preparation (pour-on formulations) and water on the localized area of spilling or being sprayed on skin, active compound works by dermal osmosis and whole body.
Water and spill preparation by active compound is dissolved in, be suspended in or emulsification to being prepared in the suitable solvent of skin tolerance or the solvent mixture.If suitable, can add other auxiliary agent, as tinting material, absorption enhancer, oxidation inhibitor, photostabilizer, tackiness agent etc.
The solvent that can mention comprises: water, alkanol, glycols, polyethylene glycols, polypropylene glycols, aromatic alcohol such as benzylalcohol, phenylethyl alcohol, phenoxyethyl alcohol, ester such as ethyl acetate, butylacetate, peruscabin, ethers, as aklylene glycol alkyl oxide (as dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether), ketone such as acetone, methylethylketone, aromatics and/or aliphatic hydrocarbon, vegetables oil or synthetic oil, DMF, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, 2,2-dimethyl-4-oxo methylene radical-1,3-dioxolane.
Tinting material comprises that all allow to be used on the animal body and can be dissolved or the tinting material that suspends.
Absorption enhancer comprises for example DMSO, diffusion oil, and as Isopropyl myristate, dipropylene glycol pelargonate, silicone oil, fatty acid ester, triglyceride level, Fatty Alcohol(C12-C14 and C12-C18).
Oxidation inhibitor is sulphite and metabisulphite, as inclined to one side Potassium hydrogen sulfite, xitix, butylhydroxy toluene, butyl hydroxyanisole, tocopherol.
Photostabilizer comprises for example Phenylbenzimidazolesulfonic acid.
Tackiness agent comprises for example derivatived cellulose, starch derivative, and polyacrylic ester, naturally occurring polymkeric substance is as alginic acid salt, gelatin.
Emulsion can be oral, applied dermally or use with the injection form.
Emulsion is water-in-oil-type or oil-in-water-type.
Being prepared as follows of they: be dissolved in active compound hydrophobic or aqueous favoring in, and by suitable emulsifying agent with this solution and another solvent phase homogenizing, and if suitable, can add other auxiliary agent, as tinting material, absorption enhancer, sanitas, oxidation inhibitor, photostabilizer, tackifier.
The hydrophobic phase (oil) that can mention comprising: paraffin oil, and silicone oil, naturally occurring vegetables oil such as sesame oil, Prunus amygdalus oil, Viscotrol C, synthetic glycerine three esters are as sad/caproic acid two glyceryl ester, triglyceride level and chain length C 8-12Vegetable fatty acid or be selected from the mixture of naturally occurring lipid acid especially with other, can contain the partial glycerol ester mixture of the saturated or unsaturated fatty acids of oh group, and C 8/ C 10The list of-lipid acid and two-glyceryl ester.
Fatty acid ester, as Stearic ethyl stearate, Di-n-butyl Adipate, lauric acid hexyl ester, the n-nonanoic acid-dipropylene glycol ester that contracts, middle long-chain branched chain fatty acid and chain length C 16-C 18The ester that forms of saturated fatty alcohol, Isopropyl myristate, Wickenol 111, chain length C 12-C 18The suffering/capronate of saturated fatty alcohol, isopropyl stearate, Oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, wax shape fatty acid ester is as synthetic duck uropygial gland fat (synthetic duckuropygeal gland fat), dibutyl phthalate, Wickenol 116, the ester mixture of a kind of ester in back and other ester.
Fatty Alcohol(C12-C14 and C12-C18), as different tridecyl alcohol, 2-Standamul G, cetyl stearyl alcohol, oleyl alcohol.
Lipid acid, for example oleic acid and composition thereof.
The aqueous favoring that can mention comprises: water, and pure as propylene glycol, glycerine, Sorbitol Powder and composition thereof.
The emulsifying agent that can mention comprises: nonionogenic tenside, polyoxyethylated castor oil for example, polyoxy ethylization dehydrated sorbitol mono-fatty acid ester, sorbitan monostearate, glyceryl monostearate, polyoxyethylene stearic acid ester, alkyl phenol polyoxyethylene glycol ether;
Amphoterics is as N-dodecyl-β-imino-disodium beclomethasone or Yelkin TTS.
Anion surfactant, as sodium lauryl sulphate, fatty alcohol ether sulphate, the monoethanolamine salt of list/dialkyl group polyglycol ether ortho-phosphoric acid ester.
Other auxiliary agent that can mention comprises: tackifier and stable emulsion material, and as carboxymethyl cellulose, methylcellulose gum and other Mierocrystalline cellulose and starch derivative, polyacrylic ester, alginate, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, the multipolymer of methylvinylether and maleic anhydride, polyoxyethylene glycol, wax, the mixture of colloid silicic acid or listed material.
But the suspension per os is used or is used with the injection liquid form through the skin approach.It is prepared as follows: activated mixture is suspended in the vehicle liquid,, adds other auxiliary agent if suitable, and as wetting agent, tinting material, absorption enhancer, sanitas, oxidation inhibitor, photostabilizer.
The carrier liq that can mention comprises all homogeneous solvents and solvent mixture.
The wetting agent that can mention (dispersion agent) comprises above-mentioned tensio-active agent.
Other auxiliary agent that can mention comprise above-mentioned those.
But semi-solid preparation per os or applied dermally.The difference of they and above-mentioned suspension and emulsion only is that their viscosity is higher.
Be the preparation semi-solid preparation, activated mixture is mixed with the carrier substance that suits, if suitable, add auxiliary agent, and mixture is processed into desired shape.
The carrier substance that can mention comprises the solid, inert material that can tolerate on all physiology.Can use inorganic or organic substance as this inert substance.Inorganic substance comprise for example sodium-chlor, carbonate, and as lime carbonate, Calcium hydrogen carbonate, aluminum oxide, silicic acid, alumina, precipitation or colloid silica, phosphoric acid salt.
Organic substance comprises for example sucrose, Mierocrystalline cellulose, and food and animal-feed, as milk powder, animal foodstuff, flour, coarse grit and starch.
Auxiliary agent comprises the sanitas of as above mentioning already, oxidation inhibitor, dyestuff.
Other suitable auxiliary agent is lubricant and antiseize paste (slip agents), Magnesium Stearate for example, stearic acid, talcum, wilkinite, can promote the material of disintegration, as starch or cross-linked polyvinylpyrrolidone, binding agent, as starch, gelatin or straight linear polyethylene pyrrolidone, and dried binding agent are as Microcrystalline Cellulose.
Active compound also can be to be present in the preparation with synergistic agent or with the form of mixtures of the active compound of other disease-resistant originality endoparasite.These active compounds comprise for example L-2,3,5, and 6-tetrahydrochysene-6-phenylimidazole and thiazole, benzoglyoxaline-amino formate, praziquantel, pyrantel, febantel.
Ready-to-use formulation comprises that concentration is 10ppm-20wt%, the active compound of preferred 0.1-10wt%.
The preparation of dilution comprises that concentration is 0.5-90wt% before using, the active compound of preferred 5-50wt%. Embodiment ANematode test in the body
The test of sheep haemonchus contortus
After parasitological incubation finished, treatment was by the sheep of haemonchus contortus experimental infection.Active compound is used by oral and/or intravenously with respective pure form.
Measure level of activity by the worm's ovum that goes out with defecate before and after the quantitative counting treatment.
If after the treatment, do not have worm's ovum fully and discharge, mean that then worm is purged or no longer produced any ovum (effective dose) by major injury so that they.
Test active compound and effective dose see the following form listed:
The embodiment of active compound number Effective dose [mg/kg] The embodiment of active compound number Effective dose [mg/kg]
1 2 4 7 9 15 41 5 5 5 5 5 5 5 49 54 67 72 73 78 82 5 5 5 5 5 5 5
Embodiment BNematode test in the body
The test of sheep trichostrongylus colubriformis
After parasitological incubation was full, treatment was by the sheep of trichostrongylus colubriformis experimental infection.Active compound is used by oral and/or intravenously with respective pure form.
Measure level of activity by the worm's ovum that goes out with defecate before and after the quantitative counting treatment.
If the treatment after, laying eggs stops fully, then mean worm be purged or be damaged to they no longer produce any ovum (effective dose).
Test active compound and active dose can be found out from following table:
The embodiment of active compound number Effective dose [mg/kg]
3 4 20 41 74 81 5 5 5 5 5 5
Preparation embodiment
Embodiment 1
7-benzyl-4a α, 5a α, 8a α, 8b α-(±)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201021
With 7.4g (0.04mol) N-benzyl maleimide and 2.4g (0.02mol) 3, the 5-dimethyl pyridine N-oxide stirred 10 hours under reflux temperature in 30ml toluene.Vacuum concentration reaction mixture then, and by silicagel column (silica gel 60-Merck, granularity: 0.04-0.063mm) the last crude product of chromatography, adopt hexanaphthene: ethyl acetate (1: 1) is as moving phase.Obtain 3.6g (theoretical value 58.0%) 7-benzyl-4a α, 5a α, 8a α, 8b α-(±)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone.
Fusing point: 123-124 ℃
1H-NMR(400MHz，CDCl 3，δ)：1.27(s，3H，C-CH 3)；1.56(d，3H；＝C-CH 3；J＝
1.6Hz)；3.94(dd，1H，-CH-；J＝9.6；7.9)；4.24(dd，1H，J＝9.6；2.4Hz)；4.57(s，
2H ,-CH 2-phenyl); 4.76 (d, 1H ,-O-CH-; J=7.9Hz); 5.74 (dd, 1H ,=CH-; J=2.4;
1.2Hz) 7.26-7.41 (2m, 5H, phenyl); 7.53 (t, 1H=CH-, J=2.4Hz) ppm
13C-NMR(100MHz，CDCl 3，δ)：17.8；24.8(-CH 3)；42.0(-CH 2)；50.1；65.7
(-CH-) 74.4 (O-CH-); 79.2 (-C-Me); 128.4 (=CMe); 131.1; 159.1 (=CH-; Heteroaryl);
127.5; 128.1; 128.7; 135.0 (=CH-; Phenyl); 172.7; 173.7 the ppm of (-C=O)
EI-MS m/z(％)：310(M +，100)；271(38)；214(62)
General formula (Ia) compound listed in the following table 53 can prepare by similar approach.
Table 53
The embodiment of formula (I) compound.
Figure C9619906201041
Figure C9619906201051
A)EI-MS or LS-MS (acid) m/z (%); Ph: phenyl; TBu: the tertiary butyl; IPr: sec.-propyl
Embodiment 40
7-ethyl-4a α, 5a α, 8a α, 8b α-(±)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] hydrochloride of furo [3,2-b] pyridines-6,8 (7H)-diketone (4)
Figure C9619906201061
Stir down, dry hydrogen chloride gas is passed into 1.5g (6.0mmol) 7-ethyl-4a α, 5a α, 8a α, 8b α-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] in the solution of furo [3,2-b] pyridines-6,8 (7H)-diketone (4) and 10ml acetone.After reacting about 20 minutes, tell the colourless hydrochloride that has been settled out and use a large amount of washing with acetones.
Obtain 1.6g (theoretical value 93.6%) 7-ethyl-4a α, 5a α, 8a α, 8b α-(±)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-dione hydrochloride.
Fusing point: 134-135 ℃
1H-NMR (300MHz, CDCl 3, 100 f ＂ symbol ＂) 0.94 (t, 3H ,-CH 3J=7.2Hz);
1.34(s，3H，C-CH 3)；1.84(d，3H；＝C-CH 3；J＝1.6Hz)；3.25-3.32(q，2H，-CH 2；
7.2Hz)；3.98(dd，1H，-CH-；J＝9.6；7.9)；4.64(dd，1H，-CH-；J＝9.6；2.4Hz)；
4.84(d，1H，-O-CH-；J＝7.9Hz)；6.46(dd，1H，＝CH-；J＝2.4；1.2Hz)；8.55(t，
1H，＝CH-；J＝2.4Hz)ppm
Embodiment 41
7-ethyl-4a α, 5a α, 8a α, 8b α-(±)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] N of furo [3,2-b] pyridines-6,8 (7H)-diketone (4) 1-methyl ammonium iodide
With 1.0g (4.0mmol) 7-ethyl-4a α, 5a α, 8a α, 8b α-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone (4) is dissolved in the 5ml acetone, and adds 1.4g (9.8mmol) methyl-iodide under room temperature.After 20 minutes, isolate institute's precipitated solid, with a large amount of washing with acetones and dry.
Obtain 0.81g (theoretical value 51.9%) N 1-methyl ammonium iodide.
1H-NMR(300MHz，CDCl 3，δ)：0.94(t，3H，-CH 3；J＝7.2Hz)；1.39(s，3H，
C-CH 3)；1.84(d，3H；＝C-CH 3；J＝1.6Hz)；3.28-3.31(q，2H，-CH 2；7.2Hz)；3.88(s，
3H，＝N+-CH 3)；4.21(dd，1H，-CH-；J＝9.6；7.9Hz)；4.68(dd，1H，-CH-；J＝9.6；
2.4Hz)；4.91(d，1H，-O-CH-；J＝7.9Hz)；6.58(dd，1H＝CH-；J＝2.4；1.2Hz)；
8.86(t，1H，＝CH-；J＝2.4Hz)ppm
EI-MS m/z(％)：263(M +-I -，100)；271(38)；122(75)
Embodiment 42
Similarly, by 5.0g (0.021mmol) 7-methyl-4a α, 5a α, 8a α, 8b α-(+/-)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone (2), 4.2g (0.030mol) methyl-iodide and 125ml acetone prepare 7-methyl-4a α, 5a α, 8a α, 8b α-(+/-)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ', 5] N of furo [3,2-b] pyridines-6,8 (7H)-diketone (2) 1-methyl ammonium iodide.The result obtains 5.6g (theoretical value 70.4%) N 1-methyl ammonium iodide.
Fusing point: 234 ℃
Embodiment 43
At 0.3g Pd (OH) 2-charcoal [Pd content 20%] exists down, with 2.0g (6.4mmol) 7-benzyl-4a α, 5a α, 8a α, 8b α-(±)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] till furo [3,2-b] pyridines-6,8 (7H)-diketone is hydrogenated to no hydrogen and absorbs in 70ml ethanol (about 4 hours).Behind the filtration catalizer, vacuum concentration total overall reaction solution, obtain 1.8g (theoretical value 99.1%) isomer mixture (3: 1), this mixture can adopt ethyl acetate to carry out silicagel column (silica gel 60-Merck, granularity: 0.04-0.063mm) chromatographic separation as moving phase.
7-benzyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Fusing point: 129-130 ℃
13C-NMR(100MHz，CDCl 3，δ)；18.1；25.3(-CH 3)；39.2；48.9；42.0(-CH 2)；26.8
61.5；50.3(-CH-)；75.7(-O-CH-)；84.8(-C-Me)；127.5；128.1；128.5；134.8
(=CH-, phenyl); 174.5; 175.0 the ppm. of (-C=O)
Embodiment 44
7-benzyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Fusing point: 115-117 ℃
13C-NMR(100MHz，CDCl 3，δ)；18.4；25.0(-CH 3)；41.7；41.8；51.2(-CH 2)；26.1；
52.0；59.7(-CH-)；76.2(-O-CH-)；86.6(-C-Me)；127.3；128.1；135.2(＝CH-；
Phenyl); 174.2; 174.6 the ppm of (-C=O)
Following compound obtains by hydrogenation embodiment (2) compound separation.
Embodiment 45
The 7-methyl isophthalic acid, 2,4a α, 5a α, 8a α, 8b α-(±)-six hydrogen-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone EI-MS m/z (%); 236 (M +, 61)
Embodiment 46
The 7-methyl isophthalic acid, 2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-1,3,4a-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201091
With 5.0g (13.3mmol) 7-methyl-4a α, 5a α, 8a α, 8b α-(+/-)-tetrahydrochysene-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] N of furo [3,2-b] pyridines-6,8 (7H)-diketone 1-methyl ammonium iodide is suspended in the 100ml methyl alcohol, and adds 0.64g (16.9mmol) NaBH under-5 ℃ in batches 4After stirring the mixture 2 hours under 0 ℃, stirring at room is about 18 hours again.Vacuum concentration total overall reaction solution is dissolved in the surplus residue of institute in the chloroform then, shakes a few hours with water.Tell organic phase, with dried over mgso and vacuum concentration.Obtain 2.8g (theoretical value 87.3%) 7-methyl isophthalic acid, 2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-1,3,4a-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone.
M.p.：124-125℃
1N-NMR(400MHz，CDCl 3，δ)1，37(s，3H，-C-CH 3)；1.57(s，3H；＝C-CH 3)2.85；2.91(2s，6H，2x-N-CH 3)；2.97；3.15(2d，2H，-C-CH aH b-；J＝9.8HZ)；3.45(dd，1H，-CH-；J＝9.9；7.7Hz)；3.55(d，1H，-CH-；J＝9.9Hz)；4.70(d，1H，-O-CH-；J＝7.7Hz)；5.29(m，1H，＝CH-)ppm
Embodiment 47
1-(2-chloroethoxy carbonyl)-1,2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-3,4a, 7-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines 6,8 (7H)-diketone
With 2.4g (9.6mmol) 7-methyl isophthalic acid, 2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-1,3,4a-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone stir in the 2-ethylene dichloride at 15ml 1, add 2.7g (19.2mmol) 1-chloroethoxy carbonyl chlorine and mixture was heated 20 minutes under reflux temperature.Added two parts of 1-chloroethoxy carbonyl chlorine at interval with 20 minutes then, every part of 1.3g (9.6mmol) stirred the mixture under reflux temperature 5 hours subsequently.Also (silica gel 60 is available from Merck by silicagel column for the vacuum concentration complete reaction mixture; Granularity: 0.04-0.063mm) purifying, adopt ethyl acetate as mobile solvent.Obtain 1.7g (theoretical value 53.9%) 1-(1-chloroethoxy carbonyl)-1,2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-3,4a, 7-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone, this product can carry out other reaction at once.
Embodiment 48
1,2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-3,4a, 7-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] hydrochloride of furo [3,2-b] pyridines-6,8 (7H)-diketone (45)
With 1.7g (5.2mmol) 1-(1-chloroethoxy carbonyl)-1,2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-3,4a, 7-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone stirs in 4ml methyl alcohol.Earlier with mixture heating up to 50-60 ℃, then stir about 30 minutes under reflux temperature then.With the hydrochloride that a small amount of ether washing precipitation goes out, obtain 1.1g (theoretical value 77.6%) 1,2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-3,4a, 7-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] hydrochloride of furo [3,2-b] pyridines-6,8 (7H)-diketone (45).
1H-NMR(400MHz，D 2O，δ)：1.42(s，3H，-C-CH 3)，1.78(s，3H；＝C-CH 3)；2.98(2s，6H，2x-N-CH 3)；3.58；3.67(2d，2H，-C-CH aH b-；J＝9.8Hz)；4.11(d，1H，-CH-；J＝9.9Hz)；4.35(dd；1H，-CH-；J＝9.9；7.7Hz)，5.03(d，1H，-O-CH-，J＝7.7Hz)；5.73(m，1H，＝CH-)ppm
Embodiment 49
1-allyloxy carbonyl-7-ethyl-1,2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
For obtaining free alkali, with 2.6g (9.1mmol) 7-ethyl-1,2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-3,4a, 7-trimethylammonium-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-dione hydrochloride and 1.4g (10.9mmol) N, N-diisopropylethylamine (" Hunig alkali ") together stirs in the mixture of 50ml water and 150ml methylene dichloride.After 10 minutes, separate organic phase, use dried over mgso.Adding 1.8g (13.6mmol) N to methylene dichloride in mutually under 0 ℃ then, N-diisopropylethylamine (" Hunig alkali ") and 1,3g (10.9mmol) allyl chlorocarbonate, and with mixture 0 ℃ of following stir about 10 minutes, stirring at room is 2 hours then.Then with organic phase water extraction twice, with dried over mgso and vacuum concentration.(silica gel 60 is available from Merck with silicagel column for remaining crude product; Granularity 0.04-0.063mm) chromatography, adopt hexanaphthene: ethyl acetate (1: 1) is as moving phase.Obtain 1.0g (theoretical value 32.9%) 1-allyloxy carbonyl-7-ethyl-1,2,4a α, 5a α, 8a α, 8b α-(+/-)-six hydrogen-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone.
M.p.87-90℃
EI-MS m/z(％)：334(M +；2)；249(M +-[H 2C＝CH-H 2C-O-CO]，100].
Prepare according to method 5a
Embodiment 50
1-methyl-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, 8b α-(+/-)-octahydro-3 α, 4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6.8 (7H)-diketone
Under the nitrogen atmosphere, 1.1g (9.6mmol) methyl-iodide is added to 2.0g (8.4mmol) contains 7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6, in the 100ml dimethyl formamide solution of 8 (7H)-diketone and sodium bicarbonate, and with mixture 80 ℃ of following stir abouts 5 hours.In reaction soln impouring water, with ethyl acetate extraction for several times, tell organic phase then, after dried over sodium sulfate, vacuum concentration.Last crude product passes through silica gel column chromatography.
LC-MS (acid) m/z (%): 283 (MH -, 100); 265 (12); 141 (37); 101 (66).
Prepare according to method 5h
Embodiment 51
1-(2-cyano ethyl)-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201121
With 2.0g (87.9mmol) 7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone and 0.5g (10.0mmol) vinyl cyanide stirring and refluxing 28 hours in 10ml ethanol.Reaction soln shakes twice with water, tells organic phase then, after with dried over sodium sulfate, and vacuum concentration.Remaining crude product is by silicagel column (silica gel 60-Merck, granularity: 0.04-0.063mm) chromatography.
LC-MS (acid) m/z (%): 306 (MH +, 100); 253 (M +-[NC-CH 2-CH 2-], 29)
Prepare according to method 5c
Embodiment 52
1-((±)-2-hydroxyl-3-isopropoxy third-1-yl)-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201131
To contain 5.0g (19.2mmol) 7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone and 0.9g (8.0mmol) (±)-2, the 40ml tetrahydrofuran solution reflux of 3-epoxypropyl isopropyl ether 24 hours.The last crude product of vacuum concentration total overall reaction solution and chromatography purification then.
LC-MS (acid) m/z (%): 369 (MH +, 100); 253 (16).
Prepare according to method 5d
Embodiment 53
1-allyloxy carbonyl-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the β of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201132
Under 0 ℃, with 2.8g (21.6mmol) N, N-diisopropylethylamine (" Hunig alkali ") is added to 2.0g (8.4mmol) 7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the β of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and 1.1g (9.6mmol) allyl chlorocarbonate are in the solution of 100ml methylene dichloride, and stirred the mixture 2 hours at 0 ℃, stirring at room is 2 hours then.Reaction soln is shaken twice with water, tell organic phase, concentrating with the dried over sodium sulfate final vacuum.(silica gel 60-Merck, granularity: 0.04-0.063mm) chromatography, the employing ethyl acetate is as moving phase by silicagel column for last crude product.Obtain 1.9g (theoretical value 73.9%) 1-allyloxy carbonyl-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the β of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone oily product.
EI-MS m/z(％)：322(M +，5)；237(100)；108(72).
Embodiment 54
1-allyloxy carbonyl-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201141
The reaction process of similar embodiment (53), adopt following raw material to carry out the N-acylation reaction 4 hours: 2.0g (8.4mmol) 7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, 8b α-(±)-
Octahydro-3 α, 4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5]
Furo [3,2-b] pyridines-6,8 (7H)-diketone 1.1g (9.6mmol) allyl chlorocarbonate 2.8g (21.6mmol) N, N-diisopropylethylamine (" Hunig alkali ") 100ml methylene dichloride
Obtain 1.6g (theoretical value 64.6%) 1-allyloxy carbonyl-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone.
Fusing point: 94-96 ℃
EI-MS m/z(％)：322(M +，6)；237(100)；108(50).
Embodiment 55
1-chloromethyl carbonyl-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
The reaction process of similar embodiment (53), adopt following raw material to carry out the N-acylation reaction 1 hour: 6.0g (23.7mmol) 7-ethyl-1,2,3,4,4a α, 5a α, 8a α, 8b α-(±)-
Octahydro-3 α, 4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5]
Furo [3,2-b] pyridines-6,8 (7H)-diketone 3.3g (28.5mmol) chloroacetyl chloride 6.6g (65.1mmol) triethylamine 60ml methylene dichloride
EI-MS m/z(％)：328(M +，8)；251(M +-[Cl-CH 2-CO]，100)；108(44).
Embodiment 56
1-(N-morpholino-methyl carbonyl)-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
0.2g (1.8mmol) triethylamine is added to contains 0.5g (1.5mmol) 1-chloromethyl carbonyl-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone ( 55) and the 5ml acetonitrile solution of 0.15g (1.8mmol) morpholine in, and this mixture of reflux 1 hour.
The vacuum concentration reaction soln, and residue is dissolved in chloroform, subsequently this mixture and water are together shaken.Separate organic phase, with dried over mgso and vacuum concentration.(silica gel 60-Merck, granularity: 0.04-0.063mm) chromatography purification, the employing ethyl acetate is as moving phase by silicagel column for last crude product.Obtain 0.25g (theoretical value 43.3%) 1-(N-morpholino methyl carbonyl)-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone.
1H-NMR(300MHz，CDCl 3，δ)：2.60(m，br.4H，-(CH 2) 2-N-)；3.77(m，br.，4H，-(CH 2) 2-O)ppm.
EI-MS m/z (%): 379 (M +, 1); 251 (M +-[CO-CH 2-N-morpholine], 1); 100 ([CH 2-N-morpholine], 100).
Prepare according to method 5e
Embodiment 57
1-(carboxyl methoxymethyl carbonyl)-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201161
With 2.0g (8.4mmol) 7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone is dissolved in the 10ml tetrahydrofuran (THF), and under 50 ℃, be added drop-wise in the 20ml anhydrous tetrahydrofuran solution of 1.4g (12.0mmol) anhydride diethylene glycol, under this temperature, continue then to stir 12 hours.Vacuum concentration total overall reaction solution is told last material and is washed several with ether subsequently.
LC-MS (acid) m/z (%): 355 (MH +, 100), 309 (12).
Embodiment 58
1-(carboxyl methoxymethyl carbonyl)-7-methyl isophthalic acid, 2,4a α, 5a α, 8a α, 8b α-(±)-six hydrogen-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201171
The reaction process of similar embodiment (57) adopted following raw material to finish N-acylation reaction: 2.0g (8.4mmol) 7-methyl isophthalic acid in 12 hours, and 2,4a α, 5a α, 8a α, 8b α-(±)-six hydrogen-3,
4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo
[3,2-b] pyridines-6,8 (7H)-diketone 1.4g (12.0mmol) anhydride diethylene glycol 30ml tetrahydrofuran (THF) LC-MS (acid) m/z (%): 353 (M-H +, 100); 237 (18) prepare according to method 5f
Embodiment 59
1-(N-benzyloxycarbonyl-N-methyl-glycyl)-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201172
Under 0 ℃, with 3.2g (25.2mmol) N, N-diisopropylethylamine (" H ü nig alkali ") and 2.1g (8.4mmol) are two, and (2-oxo-3-oxazolidinyl) Phosphonium acyl chlorides (bis (2-oxo-3-oxazolidinyl)-phosphonium acid chloride) (BOP-Cl) is added to and contains 2.0g (8.4mmol) 7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] in the 100ml dichloromethane solution of furo [3,2-b] pyridines-6,8 (7H)-diketone and 1.7g (7.6mmol) N-carbobenzoxy-(Cbz)-sarkosine (Z-Sar-OH), and mixture stirred 30 minutes down at 0 ℃, stirred 18 hours under the room temperature then.Reaction soln shakes twice with water, tells organic phase, with dried over sodium sulfate and vacuum concentration.(LiChroprepRP-18-Merck, granularity: 0.4-0.063mm) chromatography, employing acetonitrile/water (4: 6) is as moving phase by LiChroprep RP-18 post for last crude product.
1H-NMR(300MHz，CDCl 3，δ)：2.98；3.08(2s，6H，2xN-CH 3)ppm.
EI-MS m/z (%): 444 (MH +4); 443 (M +, 15); 237 (M +-[COCH 2-NMe-CO-O-benzyl]; 38); 209 (20); 91 (benzyls; 100).
Prepare according to method 5g
Embodiment 60
1-tribromo-acetyl base aminocarboxyl-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Under 0 ℃, 1.6g (8.4mmol) trichloroacetyl isocyanate is added to 2.0g (8.4mmol) 7-methyl isophthalic acid, 2; 3,4,4a α; 5a α, 8a α, the α of 8b α-(±)-octahydro-3; 4a-dimethyl-6H-pyrrolo-[3 '; 4 ': 4,5] furo [3,2-b] pyridine-6; in the 30ml acetonitrile solution of 8 (7H)-diketone, and mixture stirred 30 minutes down at 0 ℃.Thereafter reaction soln and water are together shaken twice, tell organic phase then, with dried over sodium sulfate and vacuum concentration.(silica gel 60-Merck, granularity: 0.04-0.063mm) chromatography purification, the employing ethyl acetate is as moving phase by silicagel column for last crude product.Obtain 1.2g (theoretical value 34.6%) 1-tribromo-acetyl base aminocarboxyl-7-methyl isophthalic acid, 2,3,4,4a α; 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 '; 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone.
EI-MS m/z(％)：391(M + -Cl，1)；355(M + -2Cl，8)；306(M +-[Cl 3CH]；19)；237(100).
Prepare according to method 5h
Embodiment 61
1-alkynes propoxycarbonyl-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
To 2.0g (8.4mmol) 7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] fed carbon dioxide gas 1 hour in pyridine-6,8 (7H)-diketone and the 30ml methyl-sulphoxide, add 1.1g (8.4mmol) propargyl bromide then.Stirring at room reaction mixture 48 hours, separate solid reduces pressure and removes volatile constituent, and with the residue ethyl acetate extraction, tells organic phase then.Use dried over sodium sulfate organic phase and vacuum concentration then, last crude product is by LiChroprep RP-18 post (LiChroprep RP-18-Merck, granularity: 0.4-0.063mm), adopt acetonitrile/water (4: 6) as moving phase.
EI-MS m/z(％)：320(M +，0.5)；237(M +-[HC≡C-CH 2-O-CO-]，20).
Separate and obtain following by-product compounds:
Embodiment 62
1-propargyl-7-methyl isophthalic acid, 2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
EI-MS m/z(％)：276(M +，5)；237(M +-[HC≡C-CH 2-]，100)，39([HC≡C-CH 2-]46).
Prepare according to method 5i
Embodiment 63
1-(4-nitrophenoxy carbonyl)-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Under 0 ℃, with 4.4g (34.8mmol) N, N-diisopropylethylamine (" H ü nig alkali ") is added to 4.0g (15.8mmol) 7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and 3.2g (15.8mmol) chloroformic acid 4-nitro phenyl ester are in the solution of 100ml methylene dichloride, and under 0 ℃, stirred the mixture 2 hours, stirring at room is 18 hours then.Reaction soln is shaken twice with water, tell organic phase, concentrating with the dried over mgso final vacuum.(silica gel 60-Merck, granularity: 0.04-0.063mm) chromatography, adopt hexanaphthene: ethyl acetate (1: 1) is as moving phase by silicagel column for last crude product.Obtain 4.0g (theoretical value 62.4%) 1-(4-nitrophenoxy carbonyl)-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the β of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone.
Fusing point: 160-167 ℃
1H-NMR (400MHz, CDCl 3, δ): 7.42,8.29 (2d, 4H, 4-NO 2-phenoxy group; J H, H=9.1Hz) ppm.
EI-MS m/z(％)：417(M +，0.29)；279(33)；223(100).
Embodiment 64
1-(N-morpholino carbonyl)-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone
Figure C9619906201211
Under the room temperature, with 0.65g (5.0mmol) N, N-diisopropylethylamine (" H ü nig alkali ") and 0.45g (5.2mmol) morpholine are added to 2.0g (4.8mmol) 1-(4-nitrophenoxy carbonyl)-7-ethyl-1,2,3,4,4a α, 5a α, 8a α, the α of 8b α-(±)-octahydro-3,4a-dimethyl-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone is in the 40ml dioxane solution, and about 48 hours of stirring and refluxing mixture.Reaction soln is shaken twice with water, tell organic phase, concentrating with the dried over mgso final vacuum.Last crude product passes through purification by silica gel column chromatography.
LC-MS (acid) m/z (%): 365 (MH +, 100); 253 (3); 141 (20); 101 (33).
Listed general formula (Ib) in the following table 54 and 55, (Ic) and (Id; R 5The compound of :-H) can prepare with similar approach. Table 54Formula (Ib) and (Id; R 5The compound of :-H) embodiment
Figure C9619906201221
Embodiment number R 1 R 2 R 3 R 4 R 5 Physical parameter
65 -H 3β-Me 4aα-Me -methyl -H mp：147-149℃
66 -H 3α-Me 4aα-Me -methyl -H mp：134-135℃
67 -H 3β-Me 4a-Me -methyl -CO-O-s-Bu mp：134-135℃
68 -H 3α-Me 4aα-Me -methyl -CO-O-s-Bu mp：84-85℃
69 -H 3β-Me 4aα-Me -ethyl -H mp：95-96℃
70 -H 3α-Me 4aα-Me -ethyl -H mp：90-93℃
71 -H 3α-Me 4aα-Me -ethyl -CO-O-allyl group mp：96-98℃
72 -H 3β-Me 4aα-Me -ethyl -CO-O-allyl group Mp: oil
73 -H 3α-Me 4aα-Me -ethyl -SO 2-NMe 2 mp：88-89℃
74 -H 3α-Me 4aα-Me -ethyl -CO-O-Me mp：129-131℃
75 -H 3β-Me 4aα-Me -ethyl -CO-O-Me mp：87℃
76 -H 3α-Me 4aα-Me -ethyl -CO-NMe 2 mp：104-105℃
77 -H 3α-Me 4aα-Me -methyl -CO-CH 2-Cl 314(M +，8) a)
78 -H 3α-Me 4aα-Me -methyl -CO-CH 2-Cl 314(M +，8) a)
79 -H 3α-Me 4aα-Me -methyl -CO-O-CH 2-Ph mp：164-165℃
80 -H 3α-Me 4aα-Me -butyl -CO-O-allyl group Mp: oil
81 -H 3β-Me 4aα-Me -methyl -CO-O-allyl group mp：88℃
A)EI-MS/LC-MS (acid) m/z (%);
Abbreviation:
The Nph:4-nitrophenyl; Ph: phenyl; Bu: butyl; Allyl group;-CH 2-CH=CH 2I-, s-and t:iso-, Zhong Heshu. Table 55Formula (Ic) and (Ie; R 5The compound of :-H) embodiment
Embodiment number R 1 R 2 R 3 R 4 R 5 Physical parameter
82 -H -Me 4aα-Me -methyl -CO-NMe-CO- NMe 2 mp：134-135℃
83 -H -Me 4aα-Me -methyl -CO-NMe 2 mp：170-171℃
84 -H -Me 4aα-Me -methyl -CO-O-allyl group mp：94-95℃
85 -H -Me 4aα-Me -ethyl -methyl mp：80-82℃
86 -H -Me 4aα-Me -ethyl -CO-O-CHCl-Me Mp: oil
87 -H -Me 4aα-Me -ethyl -H hydrochloride Mp: oil
Abbreviation:
Me: methyl; Ph: phenyl; Bu: butyl; Allyl group :-CH 2-CH=CH 2I-, s-and t:iso-, Zhong Heshu.
Formula (II) initial substance
Embodiment (II-1)
3,5-dimethyl-pyridine N-oxides
68.6ml hydrogen peroxide (30% concentration) is added drop-wise to 73.5g (0.68mol) 3, and the 5-lutidine and down stirs mixture 3 hours at 70-80 ℃ in the 410ml glacial acetic acid solution.Add 48ml hydrogen peroxide (30% concentration) again and further stirred the mixture 9 hours at 70-80 ℃.For aftertreatment, the total overall reaction material can be adjusted to alkalescence with strong caustic, utilize chloroform to shake extraction.Tell organic phase and use dried over sodium sulfate, vacuum concentration then.Last crude product and chloroform/hexanes mixtures be stirred crystallization together.
Obtain 53.6g (theoretical value 63.4%) 3,5-dimethyl-pyridine N-oxides.
1H-NMR (400MHz, CDCl 3, δ): 2.27 (s, 6H, C-CH 3); 6.94; 7.92 (2xt, 3H; Heteroaryl) ppm.
EI-MS m/z(％)：123(M +，100)；107(M +-0.5).
Embodiment (II-2)
Similarly, adopt following feedstock production 3,5-parvoline N-oxide compound:
30.9g (0.22mol) 3, the 5-parvoline
39ml hydrogen peroxide (30% concentration)
The 137ml glacial acetic acid
The result obtains 33.8g (theoretical value 97.8%) 3,5-parvoline N-oxide compound.
1H-NMR (400MHz, CDCl 3, δ): 1.25 (t, 6H, 2x-CH 3J=7.6Hz); 2.60 (q, 4H, 2x-CH 2-; J=7.6Hz); 6.98,7.96 (2xt, 3H; Heteroaryl) ppm.
Embodiment (II-3)
Similarly, adopt following feedstock production 2-phenyl-3-PICOLINE N-OXIDES:
30.9g (0.18mol) 2-phenyl-3-methyl-pyridine
32ml hydrogen peroxide (30% concentration)
The 112ml glacial acetic acid
The result obtains 38.5g (theoretical value 85.9%) 2-phenyl-3-methyl-pyridine N-oxides.
1H-NMR (300MHz, CDCl 3, δ): 2.11 (s, 3H, heteroaryl-C H 3); 7.13-7.54 (3m, 7H, phenyl-H/ heteroaryl- H); 8.24 (m, 1H, heteroaryl- H) ppm.
Formula (III) initial substance
Embodiment (III-1)
N-morpholinyl maleimide
Figure C9619906201241
With 24.3g (0.15mol) (E/Z)-N-morpholino maleinamic acid and 100g diacetyl oxide and 1.0g anhydrous sodium acetate together stirred under 100 ℃ 1 hour.Then complete reaction mixture is poured in the frozen water, stir about is 18 hours under the room temperature, uses dichloromethane extraction.After telling organic phase, use dried over sodium sulfate, vacuum concentration subsequently, (silica gel 60-Merck, granularity: 0.04-0.063mm) chromatography purification, adopt hexanaphthene: ethyl acetate (1: 1) is a moving phase to last crude product by silicagel column.Obtain 7.7g (theoretical value 35.2%) N-morpholino maleimide.
Fusing point: 104-105 ℃ 1H-NMR (400MHz, CDCl 3, δ): 3.30 (t, 4H ,-CH 2-N-CH 2J=4.4Hz); 3.83 (t4H ,-CH 2-O-CH 2-; J=4.4Hz); 6.64 (s, 2H, 2x=CH-) ppmEI-MS m/z (%); 1.82 (M +, 100) Embodiment (III-2)N-cyclopropyl maleimide
Figure C9619906201251
21.6g (0.22mol) maleic anhydride suspension in the 300ml methylene dichloride, had been added dropwise to 16.0g (0.22mol) cyclopropylamine then in 5 minutes under 0 ℃.After the stirring at room reaction mixture 16 hours, it is cooled to 0 ℃ adds several dimethyl formamides, in 30 minutes, add 20ml (0.24mol) oxalyl chloride then.
After mixture at room temperature further stirred 8 hours, vacuum was removed excessive oxalul chloride, and last crude product is dissolved in the 180ml methylene dichloride again, added 30.6ml (0.22mol) triethylamine.Stirring at room reaction mixture 1.5 hours filters then, and filtrate is washed with 1N HCl.After telling organic phase it is used dried over sodium sulfate, vacuum concentration subsequently, (silica gel 60-Merck, granularity: 0.04-0.063mm) chromatography purification, adopt hexanaphthene: ethyl acetate (1: 1) is a moving phase to last crude product by silicagel column.Obtain 11.3g (theoretical value 37.7%) N-cyclopropyl maleimide. 1H-NMR(400MHz，CDCl 3，δ)；0.84-0.98(m，4H，-CH 2-CH 2-)；2.49-2.56(m，1H，-CH-)；6.64(s，2H，2x＝CH-)ppmEI-MS m/z(％)：137(M +，19)
Listed compound can prepare with similar approach in the following table 56:
Table 56
Formula (III) initial substance
Figure C9619906201261
Figure C9619906201271
A) 1H-NMR (400MHz, CDCl 3), be unit with ppm; EI-or FAB-MSm/z (%)
The preparation embodiment that replaces maleinamic acid as the N-of precursor
(E/Z)-N-morpholino-maleinamic acid
Under 0 ℃, the amino morpholine of N-that is dissolved in the 10ml methylene dichloride is added drop-wise in the 290ml dichloromethane solution of 14.8g (0.15mol) maleic anhydride, at room temperature stirred the mixture then about 18 hours.Vacuum concentration total overall reaction solution, obtain 25.3g (theoretical value 83.1%) (E/Z)-N-morpholino maleinamic acid, this product need not to be further purified and can directly react.
Fusing point:＞177 ℃ (decomposition) 1H-NMR (400MHz, DMSO-d 6, δ): 2.72; 2.77 (2t, 4H ,-CH 2-N-CH 2-, J=4.4Hz); 3.64; 3.66 (t, 4H ,-CH 2-O-CH 2-; J=4.4Hz); 6.06; 6.20; 6.30; 6.80 (4d, 4H, 4x=CH-); 9.12,9.78 (2s, 2H ,-NH-); 13.68 (br s, 1H ,-CO-OH) ppmFAB-MS m/z (%); 201 (M -+ H, 100), 154 (90); 136 (66)
Listed compound can prepare with similar approach in the following table 57: Table 57
Figure C9619906201301
Figure C9619906201302
A) 1H-NMR (400MHz, DMSO-d 6), be unit with ppm; EI-or FAB-MSm/z (%)

Claims (12)

1. the compound of general formula (I) and its optically active isomer, racemic modification and salt, Wherein
Figure C9619906200022
Expression
Figure C9619906200023
Wherein
R 1Represent hydrogen, have the straight or branched alkyl of 4 carbon atoms of as many as, C 3-6-cycloalkyl, aryl-C 1-2-alkyl is selected from phenyl, naphthyl, tetralyl, 2, and the aryl of 3-indanyl, fluorenyl has 57 yuan of rings and 1-3 identical or different heteroatomic heteroaryl that is selected from oxygen, sulphur or nitrogen, heteroaryl-C 1-2-alkyl, they can be optionally substituted,
R 2And R 3Represent hydrogen independently of one another, have the straight or branched alkyl of as many as 4 carbon atoms, have the C of 1-9 halogen atom 1-4Haloalkyl, hydroxyalkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-2The mercapto alkyl, C 1-2Alkylthio alkyl, C 1-2-alkyl sulfinyl alkyl, C 1-2-alkyl sulphonyl alkyl, aminoalkyl group, C 1-6The alkylamino alkyl, C 1-6Dialkyl aminoalkyl, C 3-6-cycloalkyl amino alkyl, C 1-6Cycloalkyl, C 1-4-alkoxy carbonyl,
R 4Represent hydrogen, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6-alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-4Alkoxy carbonyl-C 1-4-alkyl, amino-C 1-6-alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6-dialkyl amido-C 1-6-alkyl, C 1-6-trialkyl ammonium-C 1-6-alkyl halide, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6Cycloalkyl, C 3-6-cycloalkyl-C 1-2-alkyl, aryl, aryl-C 1-2-alkyl has 57 yuan of rings and 1-3 identical or different heteroatomic heteroaryl that is selected from oxygen, sulphur or nitrogen, has 57 yuan of rings and 1-3 identical or different heteroatomic heteroaryl-C that is selected from oxygen, sulphur or nitrogen 1-2-alkyl, these groups can be optionally substituted, amino, C 1-4-alkylamino, C 3-7Cycloalkyl amino,
Its precondition is
R 1Represent hydrogen and
R 2And R 3During represent methylidene
R 4Represent methylidene not, normal-butyl, phenyl; 2-, 3-or 4-aminomethyl phenyl; 2-, 3-or 4-chloro-phenyl-; 2-, 3-or 4-fluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chloro-phenyl-, 3-chloro-4-fluorophenyl; 2-, 3-or 4-nitrophenyl, 4-p-methoxy-phenyl or Alpha-Naphthyl,
Figure C9619906200031
Expression
Figure C9619906200032
Or
Wherein
R 1Represent hydrogen, have the straight or branched alkyl of as many as 4 carbon atoms, C 3-6-cycloalkyl, aryl-C 1-2-alkyl is selected from phenyl, naphthyl, tetralyl, 2, and the aryl of 3-indanyl, fluorenyl has 5-7 unit ring and 1-3 identical or different heteroatomic heteroaryl that is selected from oxygen, sulphur or nitrogen, heteroaryl-C 1-2-alkyl, they are optional the replacement,
R 2And R 3Represent hydrogen independently of one another, have the straight or branched alkyl of as many as 4 carbon atoms, have the C of 1-9 halogen atom 1-4Haloalkyl, hydroxyalkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-2The mercapto alkyl, C 1-2Alkylthio alkyl, C 1-2-alkyl sulfinyl alkyl, C 1-2-alkyl sulphonyl alkyl, aminoalkyl group, C 1-6The alkylamino alkyl, C 1-6Dialkyl aminoalkyl, C 3-6-cycloalkyl amino alkyl, C 3-6Cycloalkyl, C 1-4-alkoxy carbonyl,
R 4Represent hydrogen, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6-alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, C 1-4Alkoxy carbonyl-C 1-4-alkyl, amino-C 1-6-alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6-alkyl, C 1-6-trialkyl ammonium-C 1-6-alkyl halide, C 2-6-alkenyl, C 2-6-alkynyl, C 3-6Cycloalkyl, C 3-6-cycloalkyl-C 1-2-alkyl, aryl, aryl-C 1-2-alkyl has 5-7 unit ring and 1-3 identical or different heteroatomic heteroaryl that is selected from oxygen, sulphur or nitrogen, has 5-7 unit ring and 1-3 identical or different heteroatomic heteroaryl-C that is selected from oxygen, sulphur or nitrogen 1-2-alkyl, these groups are optional replacement, amino, C 1-4-alkylamino, C 1-4-dialkyl amido, C 3-7Cycloalkyl amino,
R 5Represent hydrogen, straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6Alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, amino-C 1-6Alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6Dialkyl amido-C 1-6Alkyl, C 1-6-trialkyl ammonium-C 1-6Alkyl halide, nitro-C 1-4Alkyl, cyano group-C 1-4Alkyl, C 1-4Alkoxy carbonyl-C 1-4Alkyl, formamyl-C 1-4-alkyl, carboxyl-C 1-4Alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-2Alkyl, aryl, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, formyl radical, C 1-4The alkoxyl group dicarbapentaborane, or representative is selected from following G 1, G 2, G 3And G 4Group:
Figure C9619906200041
Wherein
R 6Represent hydrogen, straight or branched C 1-6Alkyl, C 3-6Cycloalkyl, aryl-C 1-2Alkyl, heteroaryl-C 1-2Alkyl, these groups can be optionally substituted,
R 6And R 7Represent 5-or 6-unit ring with the atom of their institute's bondings, they can be randomly by oxygen, sulphur, and inferior sulfonyl or alkylsulfonyl are interrupted, and are optionally substituted,
R 7Represent hydrogen, straight or branched C 1-6Alkyl, C 2-4-alkenyl, C 3-6-cycloalkyl, C 3-6-cycloalkyl-C 1-2-alkyl, and the optional aryl that replaces of representative, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, or R 8Represent hydrogen or methyl,
But representation carboxy, thiocarboxyl group ,-C=CH-NO 2,-C=CH-CN ,-C=N-R 9, inferior sulfonyl, alkylsulfonyl ,-P (O)-OR 10Or P (S)-OR 10
R 9Represent hydrogen, hydroxyl, C 1-4Alkoxyl group, C 1-4Alkyl-carbonyl, halo-C 1-4Alkyl-carbonyl, C 1-4Alkyl sulphonyl, nitro or cyano group and
R 10Represent hydrogen or C 1-4Alkyl and
Q represents straight or branched C 1-6Alkyl, halo-C 1-6Alkyl, hydroxyl-C 1-6Alkyl, C 1-4The alkanoyloxy alkyl, C 1-2Alkoxyalkyl, mercapto alkyl, C 1-2Alkylthio alkyl, C 1-2Alkyl sulfinyl alkyl, C 1-2The alkyl sulphonyl alkyl, carboxyalkyl, formamyl alkyl, amino-C 1-6Alkyl, C 1-6-alkylamino-C 1-6Alkyl, C 1-6-dialkyl amido-C 1-6Alkyl, guanidine radicals-C 1-6-alkyl, this group can be randomly replaced by 1 or 2 carbobenzoxy-(Cbz), tert-butoxycarbonyl or by 1,2,3 or 4 C 1-2Alkyl group replaces, C 1-4The alkoxycarbonyl amino alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, aryl, aryl-C 1-2-alkyl, heteroaryl or heteroaryl-C 1-2Alkyl, these groups are optional the replacement, or randomly representative is selected from following G 5And G 6Group: R 11-Y-(G 5) Wherein
Figure C9619906200053
But representation carboxy, thiocarboxyl group or alkylsulfonyl, Y represents oxygen, sulphur or-NR 12, R 11, when Y represents nitrogen, can represent the cyclic amino that connects by the nitrogen-atoms key,
R 11And R 12Represent hydrogen independently of one another, straight or branched C 1-6-alkyl, C 2-6Alkenyl, C 2-6Alkynyl, C 3-6Cycloalkyl, C 3-6-cycloalkyl-C 1-2Alkyl, aryl, aryl-C 1-2-alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, they are optional the replacement, perhaps
R 11And R 12Represent 5-with adjacent nitrogen atom, 6-or 7-unit carbocyclic ring ring system, or represent 7 to 10-bicyclic ring systems of unit, these rings also can be randomly by oxygen, sulphur, inferior sulfonyl, alkylsulfonyl, carbonyl ,-N-O ,-N=,-NR 14-or be interrupted by quaternary nitrogen, and be optionally substituted,
R 13Represent hydrogen or C 1-4Alkyl,
R 14Represent hydrogen, straight or branched C 1-6-alkyl, C 2-6-alkenyl, C 2-6-alkynyl, C 3-8-cycloalkyl, C 3-8-cycloalkyl-C 1-2-alkyl, C 1-4-alkoxy carbonyl, C 1-4-alkyl-carbonyl, C 3-6-naphthene base carbonyl, cyano group, aryl, aryl-C 1-2Alkyl, heteroaryl, heteroaryl-C 1-2-alkyl, they can be optionally substituted.
2. general formula (Ia) 4a of (i) in the preparation claim 1,5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] method of furo [3,2-b] pyridines-6,8 (7H)-derovatives and salt thereof:
Wherein
R 1, R 2, R 3And R 4Definition with claim 1,
It is characterized by:
If a) suitable in the presence of thinner, make the pyridine N-oxides of general formula (II):
Wherein
R 1, R 2And R 3Definition described with claim 1,
React with general formula (III) maleimide:
Figure C9619906200072
Wherein
R 4Definition described with claim 1.
The preparation claim 1 in (ii) general formula (Ib) and (Ic) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] method of furo [3,2-b] pyridines-6,8 (7H)-derovatives and salt thereof:
Figure C9619906200073
Wherein:
R 1, R 2, R 3, R 4And R 5Definition with claim 1,
It is characterized by:
In first reactions steps, in the presence of appropriate catalyst, with general formula (Ia) 4a that claim 2 obtains, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives hydrogenation:
Figure C9619906200081
Wherein
R 1, R 2, R 3And R 4Definition with claim 1,
Form general formula (Id) and (Ie) shown in 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives:
Wherein
R 1, R 2, R 3And R 4Definition the same,
Perhaps
For selectivity prepares general formula (Ie) derivative and salt thereof, at first, if suitable in the presence of thinner, at first the methyl halide with general formula (Ia) derivative and general formula (IV) reacts:
Me-Hal (IV)
Wherein Hal represents halogen,
The formed logical formula V N of hydrogenation in the presence of suitable diluent then 1-methyl ammonium halide:
Figure C9619906200091
Follow general formula (VI) N with gained 1The N of-methyl-derivatives 1Demethylation on the atom:
Figure C9619906200092
Wherein
R 1, R 2, R 3And R 4Definition the same,
Form (Ie) compound, thereafter,
In second reactions steps, with the general formula (Id) of gained and (Ie) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives:
Wherein
R 1, R 2, R 3And R 4Definition the same,
If if a) suitable in the presence of the thinner and suitablely in the presence of the alkali reaction auxiliary agent, react with general formula (VII) compound:
R 5-E (VII)
Wherein
R 5Define the same and
E represents the electrophilic leavings group, or
B) with the reaction of general formula (VIII) compound:
Figure C9619906200102
Wherein
The acceptor groups that A representative is suitable and
R 8And R 13Definition with claim 1,
Perhaps it is characterized in that
C) if suitable in the presence of catalyzer or in the presence of the alkali reaction auxiliary agent, if suitable in the presence of thinner with general formula (IX) epoxide reaction:
Wherein
R 5Definition described with claim 1, perhaps
D) if suitable in the presence of catalyzer, if if suitable in the presence of acid binding agent and suitablely in the presence of thinner, react with general formula (X) compound:
Wherein
G, the definition of Q and X is with claim 1, and
The leavings group that the W representative is suitable,
Perhaps it is characterized in that
For the preparation general formula (Ib) and (Ic) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives and salt thereof
Group wherein
Figure C9619906200112
Representation carboxy,
E) if suitable in the presence of catalyzer, and if suitablely in the presence of thinner, react with general formula (XI) carboxylic acid anhydride:
(Q-C＝O) 2O (XI)
Wherein
The definition of Q is described with claim 1, or
F) if suitable in the presence of catalyzer, if if suitable in the presence of acid binding agent and suitable in the presence of thinner with general formula (XII) aminoderivative or its activated carboxyl derivatives reaction:
Wherein
G, Q, X, R 6, R 7And R 8Definition with claim 1, or
G) if suitable in the presence of catalyzer, if if suitable in the presence of acid binding agent and suitable in the presence of thinner with general formula (XIII) or (XIV) compound reaction:
R 11-N＝C＝X(XIII)
Wherein
Radicals R 11, G 1, X, X 1With the definition of Y with claim 1,
Perhaps it is characterized in that
For the preparation general formula (Ib) and (Ic) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridine-6,8 (7H)-derovatives and salt thereof
Group wherein Representation carboxy and Y represent oxygen,
H) in the 3rd reactions steps, and the alkaline carbonate of carbonic acid gas and general formula (XV) reaction:
M 2CO 3 (XV)
Wherein
M represents the monovalent base metallic cation,
Then, in the 4th reactions steps, with the general formula (XVI) of gained and (XVII) an alkali metal salt of compound:
Wherein
Radicals R 1, R 2, R 3And R 4Definition with claim 1,
M represents a metallic cation Equivalent that connects with the salt form key,
If if suitable the alkali reaction auxiliary agent and suitable in the presence of thinner with general formula (VIIa) alkylation reactions:
R 11-Hal (VIIa)
Wherein
R 11Definition with claim 1 and
Hal represents halogen,
Perhaps it is characterized in that:
I) with general formula (If) and (Ig) 1,2,3,4,4a, 5a, 8a, 8b-octahydro-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-diketone and/or 1,2,4a, 5a, 8a, 8b-six hydrogen-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives:
Figure C9619906200132
Wherein
Radicals R 1, R 2, R 3, R 4, G, the definition of W and X is with claim 1,
If suitable in the presence of catalyzer, if if suitable in the presence of the acid binding agent and suitablely in the presence of thinner, react with general formula (XVIII) compound:
R 11-Y-H (XVIII)
Wherein
Radicals R 11With the definition of Y with claim 1.
4. according to the method for claim 3, the Hal in its formula of (IV) represents fluorine, chlorine, bromine or iodine.
5. according to the method for claim 3, the A in its formula of (VIII) represents nitro, nitrile, formamyl or R 13-O-CO-.
6. according to the method for claim 3, the W in its formula of (X) represents halogen, alkoxyl group, alkylthio or aryloxy.
7. according to the method for claim 3, the M in its formula of (XV) represents lithium, sodium, potassium or caesium.
8. according to the method for claim 7, the M in its formula of (XV) represents potassium or caesium.
9. according to the method for claim 3, the Hal in its formula of (VIIa) represents fluorine, chlorine, bromine or iodine.
10. Endoparasiticidal agent composition is characterized by and comprises the described formula of at least a claim 1 (I) 4a, 5a, and 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives.
11. the preparation method of Endoparasiticidal agent composition is characterized in that formula (I) 4a with claim 1,5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] furo [3,2-b] pyridines-6,8 (7H)-derovatives mixes with extender and/or surface active agent composition.
12. the formula of claim 1 (I) 4a, 5a, 8a, 8b-tetrahydrochysene-6H-pyrrolo-[3 ', 4 ': 4,5] application of furo [3,2-b] pyridines-6,8 (7H)-derovatives in the preparation Endoparasiticidal agent composition.
CN96199062A 1995-10-19 1996-10-07 4a,5a,8a,8b-tetrahydro-6H-pyrrolo [3',4' : 4,5] furo (3,2-b] pyridine-6,8 [7H]-dione derivatives for use in controlling endoparasites and method Expired - Fee Related CN1111535C (en)

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